OA19551A - FXR (NR1H4) modulating compounds. - Google Patents
FXR (NR1H4) modulating compounds. Download PDFInfo
- Publication number
- OA19551A OA19551A OA1201800479 OA19551A OA 19551 A OA19551 A OA 19551A OA 1201800479 OA1201800479 OA 1201800479 OA 19551 A OA19551 A OA 19551A
- Authority
- OA
- OAPI
- Prior art keywords
- compound
- fxr
- pharmaceutically acceptable
- liver
- mixture
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 194
- 102100020059 NR1H4 Human genes 0.000 title claims abstract description 19
- 101700077249 NR1H4 Proteins 0.000 title abstract description 7
- 101700056534 farnesoid X receptors Proteins 0.000 title abstract description 7
- 230000000051 modifying Effects 0.000 title description 31
- 201000010099 disease Diseases 0.000 claims abstract description 49
- 239000000203 mixture Substances 0.000 claims description 107
- 210000004185 Liver Anatomy 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 31
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 230000001404 mediated Effects 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000005551 pyridylene group Chemical group 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 20
- 230000001684 chronic Effects 0.000 claims description 18
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 18
- 206010053219 Non-alcoholic steatohepatitis Diseases 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- 230000001587 cholestatic Effects 0.000 claims description 12
- 150000002632 lipids Chemical class 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 201000004044 liver cirrhosis Diseases 0.000 claims description 9
- 229910006069 SO3H Inorganic materials 0.000 claims description 8
- 230000000414 obstructive Effects 0.000 claims description 8
- 230000001154 acute Effects 0.000 claims description 7
- 230000003463 hyperproliferative Effects 0.000 claims description 7
- 200000000018 inflammatory disease Diseases 0.000 claims description 7
- 230000003211 malignant Effects 0.000 claims description 7
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 6
- 102000004895 Lipoproteins Human genes 0.000 claims description 6
- 108090001030 Lipoproteins Proteins 0.000 claims description 6
- 201000001320 atherosclerosis Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 206010058108 Dyslipidaemia Diseases 0.000 claims description 5
- 210000001035 Gastrointestinal Tract Anatomy 0.000 claims description 5
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 230000003176 fibrotic Effects 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 201000010874 syndrome Diseases 0.000 claims description 5
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 4
- 208000007342 Diabetic Nephropathy Diseases 0.000 claims description 4
- 208000001636 Diabetic Neuropathy Diseases 0.000 claims description 4
- 206010061835 Diabetic nephropathy Diseases 0.000 claims description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- 208000006454 Hepatitis Diseases 0.000 claims description 4
- 206010073071 Hepatocellular carcinoma Diseases 0.000 claims description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 4
- 208000008338 Non-alcoholic Fatty Liver Disease Diseases 0.000 claims description 4
- 108009000135 Nonalcoholic fatty liver disease Proteins 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 201000010897 colon adenocarcinoma Diseases 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000004761 fibrosis Effects 0.000 claims description 4
- 231100000283 hepatitis Toxicity 0.000 claims description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 4
- 238000002271 resection Methods 0.000 claims description 4
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 4
- 206010000891 Acute myocardial infarction Diseases 0.000 claims description 3
- 208000009956 Adenocarcinoma Diseases 0.000 claims description 3
- 206010019641 Hepatic cirrhosis Diseases 0.000 claims description 3
- 206010019663 Hepatic failure Diseases 0.000 claims description 3
- 206010061255 Ischaemia Diseases 0.000 claims description 3
- 206010061227 Lipid metabolism disease Diseases 0.000 claims description 3
- 208000007903 Liver Failure Diseases 0.000 claims description 3
- 238000002512 chemotherapy Methods 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 231100000835 liver failure Toxicity 0.000 claims description 3
- 208000007788 Acute Liver Failure Diseases 0.000 claims description 2
- 206010000804 Acute hepatic failure Diseases 0.000 claims description 2
- 201000011497 Barrett's esophagus Diseases 0.000 claims description 2
- 206010004137 Barrett's oesophagus Diseases 0.000 claims description 2
- 206010048832 Colon adenoma Diseases 0.000 claims description 2
- 206010012680 Diabetic neuropathy Diseases 0.000 claims description 2
- 231100000836 acute liver failure Toxicity 0.000 claims description 2
- 230000001613 neoplastic Effects 0.000 claims description 2
- 239000000546 pharmaceutic aid Substances 0.000 claims description 2
- 206010004661 Biliary cirrhosis primary Diseases 0.000 claims 4
- 201000002728 primary biliary cirrhosis Diseases 0.000 claims 4
- 208000003167 Cholangitis Diseases 0.000 claims 1
- 230000027455 binding Effects 0.000 abstract description 39
- 230000015572 biosynthetic process Effects 0.000 abstract description 32
- 239000000556 agonist Substances 0.000 abstract description 23
- 238000000034 method Methods 0.000 abstract description 22
- 238000003786 synthesis reaction Methods 0.000 abstract description 21
- 230000002194 synthesizing Effects 0.000 abstract description 21
- 102000006255 nuclear receptors Human genes 0.000 abstract description 16
- 108020004017 nuclear receptors Proteins 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 92
- 239000000243 solution Substances 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 230000002401 inhibitory effect Effects 0.000 description 53
- 239000003112 inhibitor Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 229910001868 water Inorganic materials 0.000 description 46
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000011780 sodium chloride Substances 0.000 description 28
- -1 -CHF2 Chemical group 0.000 description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 25
- 210000004027 cells Anatomy 0.000 description 23
- 239000003446 ligand Substances 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 230000002829 reduced Effects 0.000 description 21
- 150000003839 salts Chemical class 0.000 description 21
- 239000003613 bile acid Substances 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 230000001965 increased Effects 0.000 description 16
- 239000012267 brine Substances 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
- 108020001756 ligand binding domains Proteins 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 230000004913 activation Effects 0.000 description 13
- 238000005755 formation reaction Methods 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- 101700047578 FGF19 Proteins 0.000 description 12
- 102100015614 FGF19 Human genes 0.000 description 12
- 210000002381 Plasma Anatomy 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 12
- 230000000069 prophylaxis Effects 0.000 description 12
- SFCGDTAPGSSNDN-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C=1C=C(C(=O)O)C=CN=1)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C=1C=C(C(=O)O)C=CN=1)O SFCGDTAPGSSNDN-UHFFFAOYSA-N 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 238000004166 bioassay Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrugs Drugs 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 11
- 208000001130 Gallstone Diseases 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- 229940121360 farnesoid X receptor (FXR) agonists Drugs 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 229910052805 deuterium Inorganic materials 0.000 description 9
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 229940024606 Amino Acids Drugs 0.000 description 8
- 229940019746 Antifibrinolytic amino acids Drugs 0.000 description 8
- 210000000941 Bile Anatomy 0.000 description 8
- WGWDNYKACGMQGS-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC1=C(C=NN1C1=C(C=C(C=C1Cl)F)Cl)C1CC1)C1(CN(C1)C1=NC=C(C(=O)O)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC1=C(C=NN1C1=C(C=C(C=C1Cl)F)Cl)C1CC1)C1(CN(C1)C1=NC=C(C(=O)O)C=C1F)O WGWDNYKACGMQGS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 229940021015 I.V. solution additive Amino Acids Drugs 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 230000003042 antagnostic Effects 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atoms Chemical group 0.000 description 8
- 230000002354 daily Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 102100016463 GPBAR1 Human genes 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 239000004698 Polyethylene (PE) Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 229940079593 drugs Drugs 0.000 description 7
- 239000008079 hexane Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000018 receptor agonist Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 230000001225 therapeutic Effects 0.000 description 7
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
- KPWYNAGOBXLMSE-UHFFFAOYSA-N 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenyl)sulfanylpropoxy]-2-propylphenoxy]butanoic acid Chemical compound CCCC1=C(O)C(C(C)=O)=CC=C1SCCCOC1=CC=C(C(C)=O)C(OCCCC(O)=O)=C1CCC KPWYNAGOBXLMSE-UHFFFAOYSA-N 0.000 description 6
- LVSSKPGZZPVJFK-UHFFFAOYSA-N C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)F)Cl)CO Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)F)Cl)CO LVSSKPGZZPVJFK-UHFFFAOYSA-N 0.000 description 6
- AKNJXGGLICEJSD-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1)F)F)C1(CN(C1)C=1C=C(C(=O)O)C=CN=1)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1)F)F)C1(CN(C1)C=1C=C(C(=O)O)C=CN=1)O AKNJXGGLICEJSD-UHFFFAOYSA-N 0.000 description 6
- ZNKGESDUKQTOIG-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)NCC(=O)O)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)NCC(=O)O)C=C1F)O ZNKGESDUKQTOIG-UHFFFAOYSA-N 0.000 description 6
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 6
- TWBYWOBDOCUKOW-UHFFFAOYSA-N Isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- XOAAWQZATWQOTB-UHFFFAOYSA-N Taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 230000001580 bacterial Effects 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 230000001939 inductive effect Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000001184 potassium carbonate Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 102100018044 AOC3 Human genes 0.000 description 5
- 206010008635 Cholestasis Diseases 0.000 description 5
- LYUYZGAHUFTWJL-UHFFFAOYSA-N ClC1=C(C=CC(=C1)O)C1(CN(C1)C=1C=C(C#N)C=CN=1)O Chemical compound ClC1=C(C=CC(=C1)O)C1(CN(C1)C=1C=C(C#N)C=CN=1)O LYUYZGAHUFTWJL-UHFFFAOYSA-N 0.000 description 5
- AIEJNILLTCAQTJ-UHFFFAOYSA-N ClC1=C(C=NO)C(=CC(=C1)F)Cl Chemical compound ClC1=C(C=NO)C(=CC(=C1)F)Cl AIEJNILLTCAQTJ-UHFFFAOYSA-N 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- CSJLBAMHHLJAAS-UHFFFAOYSA-N Diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 5
- 101710045222 GPBAR1 Proteins 0.000 description 5
- 210000000936 Intestines Anatomy 0.000 description 5
- 229940040692 Lithium Hydroxide Monohydrate Drugs 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 201000001883 cholelithiasis Diseases 0.000 description 5
- 231100000359 cholestasis Toxicity 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 108090000376 fibroblast growth factor 21 Proteins 0.000 description 5
- 102000003973 fibroblast growth factor 21 Human genes 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 230000002443 hepatoprotective Effects 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 230000000968 intestinal Effects 0.000 description 5
- 239000007758 minimum essential media Substances 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- XBUXXJUEBFDQHD-SFTDATJTSA-N 4-[(1R,2R)-2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]cyclopropyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1[C@H]1[C@H](C=2C(=CC(OCC=3C(=NOC=3C3CC3)C=3C(=CC=CC=3Cl)Cl)=CC=2)Cl)C1 XBUXXJUEBFDQHD-SFTDATJTSA-N 0.000 description 4
- 101700033220 AOC3 Proteins 0.000 description 4
- 210000004369 Blood Anatomy 0.000 description 4
- GAVGYRAGBGVASR-UHFFFAOYSA-N BrC1=C(C=C(O[Si](C)(C)C(C)(C)C)C=C1)Cl Chemical compound BrC1=C(C=C(O[Si](C)(C)C(C)(C)C)C=C1)Cl GAVGYRAGBGVASR-UHFFFAOYSA-N 0.000 description 4
- NPLISPOULZRKEC-UHFFFAOYSA-N ClC1=C(C(=NO)Cl)C(=CC(=C1)F)Cl Chemical compound ClC1=C(C(=NO)Cl)C(=CC(=C1)F)Cl NPLISPOULZRKEC-UHFFFAOYSA-N 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N Dess–Martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 101700058973 GAL4 Proteins 0.000 description 4
- AFLFKFHDSCQHOL-IZZDOVSWSA-N GFT505 Chemical compound C1=CC(SC)=CC=C1C(=O)\C=C\C1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1 AFLFKFHDSCQHOL-IZZDOVSWSA-N 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N Glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 229960003180 Glutathione Drugs 0.000 description 4
- 108010024636 Glutathione Proteins 0.000 description 4
- 229940088597 Hormone Drugs 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 101710015850 LGALS4 Proteins 0.000 description 4
- 102100011539 LGALS4 Human genes 0.000 description 4
- 108090000865 Liver X Receptors Proteins 0.000 description 4
- 102000004311 Liver X Receptors Human genes 0.000 description 4
- 241000282567 Macaca fascicularis Species 0.000 description 4
- 230000036740 Metabolism Effects 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 229940067631 Phospholipids Drugs 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N Pioglitazone Chemical class N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M Sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 4
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 4
- 230000002378 acidificating Effects 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 230000003834 intracellular Effects 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000002609 media Substances 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 230000035786 metabolism Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000006011 modification reaction Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000001105 regulatory Effects 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 102000003995 transcription factors Human genes 0.000 description 4
- 108090000464 transcription factors Proteins 0.000 description 4
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 4
- DTHNMHAUYICORS-KTKZVXAJSA-N 107444-51-9 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 3
- LTHOTTCJGDQVEF-UHFFFAOYSA-N 2-(3-hydroxyazetidin-1-yl)pyridine-4-carbonitrile Chemical compound C1C(O)CN1C1=CC(C#N)=CC=N1 LTHOTTCJGDQVEF-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- BYTNEISLBIENSA-MDZDMXLPSA-N 3-[(E)-2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-propan-2-yl-1,2-oxazol-4-yl]methoxy]phenyl]ethenyl]benzoic acid Chemical compound CC(C)C=1ON=C(C=2C(=CC=CC=2Cl)Cl)C=1COC(C=C1Cl)=CC=C1\C=C\C1=CC=CC(C(O)=O)=C1 BYTNEISLBIENSA-MDZDMXLPSA-N 0.000 description 3
- 101710027066 ALB Proteins 0.000 description 3
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 3
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 3
- 229960000583 Acetic Acid Drugs 0.000 description 3
- 241001088417 Ammodytes americanus Species 0.000 description 3
- 241001553178 Arachis glabrata Species 0.000 description 3
- 229950010015 Bertilimumab Drugs 0.000 description 3
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 3
- 210000000013 Bile Ducts Anatomy 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- WHHXCOXUOLCYSG-UHFFFAOYSA-N C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)F)Cl)C(=O)OCC Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)F)Cl)C(=O)OCC WHHXCOXUOLCYSG-UHFFFAOYSA-N 0.000 description 3
- 102100005862 CCR2 Human genes 0.000 description 3
- 108060001122 CRTISO Proteins 0.000 description 3
- 102000012234 Cannabinoid receptor type 1 Human genes 0.000 description 3
- 108050002726 Cannabinoid receptor type 1 Proteins 0.000 description 3
- 229960001091 Chenodeoxycholic Acid Drugs 0.000 description 3
- BHQCQFFYRZLCQQ-OELDTZBJSA-N Cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 3
- 239000004380 Cholic acid Substances 0.000 description 3
- BMIKSEZPOBHKOJ-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)O)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)O)C=C1F)O BMIKSEZPOBHKOJ-UHFFFAOYSA-N 0.000 description 3
- KJZKXTMRYZAFGL-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)NCCS(=O)(=O)O)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)NCCS(=O)(=O)O)C=C1F)O KJZKXTMRYZAFGL-UHFFFAOYSA-N 0.000 description 3
- BNTXXTIADVQHED-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)O)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)O)C=C1F)O BNTXXTIADVQHED-UHFFFAOYSA-N 0.000 description 3
- UAVZUMPZGUKXMD-UHFFFAOYSA-N ClCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl Chemical compound ClCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl UAVZUMPZGUKXMD-UHFFFAOYSA-N 0.000 description 3
- 206010011401 Crohn's disease Diseases 0.000 description 3
- YWNIEUHLKKKRFM-UHFFFAOYSA-N FC=1C(=NC=C(C(=O)OC)C=1)N1CC(C1)O Chemical compound FC=1C(=NC=C(C(=O)OC)C=1)N1CC(C1)O YWNIEUHLKKKRFM-UHFFFAOYSA-N 0.000 description 3
- 101710042131 GCG Proteins 0.000 description 3
- 102100003818 GCG Human genes 0.000 description 3
- LJQLCJWAZJINEB-UHFFFAOYSA-N Hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F LJQLCJWAZJINEB-UHFFFAOYSA-N 0.000 description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 3
- 102100005677 KLB Human genes 0.000 description 3
- 101710016350 KLB Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 108060001084 Luciferase family Proteins 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 108009000330 Matrix Metalloproteinases Proteins 0.000 description 3
- 108020004999 Messenger RNA Proteins 0.000 description 3
- 102100007521 NCOA1 Human genes 0.000 description 3
- 101700068042 NCOA1 Proteins 0.000 description 3
- FSQOSGXCDJPHQN-UHFFFAOYSA-N O=C1CN(C1)C=1C=C(C#N)C=CN=1 Chemical compound O=C1CN(C1)C=1C=C(C#N)C=CN=1 FSQOSGXCDJPHQN-UHFFFAOYSA-N 0.000 description 3
- 108070000031 Orphan receptors Proteins 0.000 description 3
- 102000016978 Orphan receptors Human genes 0.000 description 3
- 102000001253 Protein Kinases Human genes 0.000 description 3
- 102100016749 SLC5A2 Human genes 0.000 description 3
- 101710040674 SLC5A2 Proteins 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 3
- 229960003080 Taurine Drugs 0.000 description 3
- 229950004996 Tipelukast Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 125000003636 chemical group Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000002559 chemokine receptor antagonist Substances 0.000 description 3
- 229950001904 chenodiol Drugs 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229960002471 cholic acid Drugs 0.000 description 3
- 235000019416 cholic acid Nutrition 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 239000012149 elution buffer Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 3
- 102000037240 fusion proteins Human genes 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl β-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 3
- 201000009673 liver disease Diseases 0.000 description 3
- 229920002106 messenger RNA Polymers 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002206 pro-fibrotic Effects 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000003909 protein kinase inhibitor Substances 0.000 description 3
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000003419 tautomerization reaction Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- YHIUPZFKHZTLSH-LXYIGGQGSA-N (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol;(2S)-5-oxopyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCC(=O)N1.C1=CC(OCC)=CC=C1CC1=CC([C@@]23O[C@@](CO)(CO2)[C@@H](O)[C@H](O)[C@H]3O)=CC=C1Cl YHIUPZFKHZTLSH-LXYIGGQGSA-N 0.000 description 2
- MRWFZSLZNUJVQW-DEOSSOPVSA-N (2S)-2-ethoxy-3-[4-[2-[2-methyl-5-(4-methylsulfanylphenyl)pyrrol-1-yl]ethoxy]phenyl]propanoic acid Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCN1C(C=2C=CC(SC)=CC=2)=CC=C1C MRWFZSLZNUJVQW-DEOSSOPVSA-N 0.000 description 2
- AHFWIQIYAXSLBA-RQXATKFSSA-N (2S,3R,4R,5S,6R)-2-[3-(1-benzothiophen-2-ylmethyl)-4-fluorophenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 description 2
- QKDRXGFQVGOQKS-CRSSMBPESA-N (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](SC)O2)O)=CC=C1Cl QKDRXGFQVGOQKS-CRSSMBPESA-N 0.000 description 2
- SCVHJVCATBPIHN-SJCJKPOMSA-N (3S)-3-[[(2S)-2-[[2-(2-tert-butylanilino)-2-oxoacetyl]amino]propanoyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid Chemical compound N([C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)COC=1C(=C(F)C=C(F)C=1F)F)C(=O)C(=O)NC1=CC=CC=C1C(C)(C)C SCVHJVCATBPIHN-SJCJKPOMSA-N 0.000 description 2
- PPUXXDKQNAHHON-BJLQDIEVSA-N (3S)-N-cyclopropyl-3-[[(2R)-3-(cyclopropylmethylsulfonyl)-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanoyl]amino]-2-oxopentanamide Chemical compound C([C@@H](C(=O)N[C@@H](CC)C(=O)C(=O)NC1CC1)N[C@@H](C=1C=CC(F)=CC=1)C(F)(F)F)S(=O)(=O)CC1CC1 PPUXXDKQNAHHON-BJLQDIEVSA-N 0.000 description 2
- FJLGEFLZQAZZCD-JUFISIKESA-N (3S,5R)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@H](O)C[C@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-JUFISIKESA-N 0.000 description 2
- ZXERDUOLZKYMJM-ZWECCWDJSA-N (4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 2
- RZVGALPEXSSYHV-UHFFFAOYSA-N (5-bromo-6-methoxypyridin-3-yl)methanol Chemical compound COC1=NC=C(CO)C=C1Br RZVGALPEXSSYHV-UHFFFAOYSA-N 0.000 description 2
- PNDKCRDVVKJPKG-WHERJAGFSA-N (5E)-8-[4-(2-butoxyethoxy)phenyl]-1-(2-methylpropyl)-N-[4-[(S)-(3-propylimidazol-4-yl)methylsulfinyl]phenyl]-3,4-dihydro-2H-1-benzazocine-5-carboxamide Chemical compound C1=CC(OCCOCCCC)=CC=C1C1=CC=C(N(CC(C)C)CCC\C(=C/2)C(=O)NC=3C=CC(=CC=3)[S@@](=O)CC=3N(C=NC=3)CCC)C\2=C1 PNDKCRDVVKJPKG-WHERJAGFSA-N 0.000 description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- MUKGOZONOWEIJV-UHFFFAOYSA-N 2,4-difluoro-N-hydroxybenzenecarboximidoyl chloride Chemical compound ON=C(Cl)C1=CC=C(F)C=C1F MUKGOZONOWEIJV-UHFFFAOYSA-N 0.000 description 2
- PDOIGRRPKSYVKH-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O.OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O PDOIGRRPKSYVKH-UHFFFAOYSA-N 0.000 description 2
- UOQMGQYMDHYXTB-UHFFFAOYSA-N 2,6-dichloro-4-fluorobenzaldehyde Chemical compound FC1=CC(Cl)=C(C=O)C(Cl)=C1 UOQMGQYMDHYXTB-UHFFFAOYSA-N 0.000 description 2
- CRIURVDGFRTCMT-UHFFFAOYSA-M 2-[2-(2-iodooxy-2-oxoethyl)phenyl]acetate Chemical compound [O-]C(=O)CC1=CC=CC=C1CC(=O)OI CRIURVDGFRTCMT-UHFFFAOYSA-M 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 description 2
- FQEYHIPPYOSPLF-UHFFFAOYSA-N 4-bromo-3-chlorophenol Chemical compound OC1=CC=C(Br)C(Cl)=C1 FQEYHIPPYOSPLF-UHFFFAOYSA-N 0.000 description 2
- SDDSJMXGJNWMJY-BRHAQHMBSA-N 7-[(2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxo-3,4,4a,5,7,7a-hexahydrocyclopenta[b]pyran-5-yl]heptanoic acid Chemical compound O1[C@](C(F)(F)C[C@@H](C)CC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 SDDSJMXGJNWMJY-BRHAQHMBSA-N 0.000 description 2
- 102100006243 ABCB11 Human genes 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 102000000452 Acetyl-CoA Carboxylase Human genes 0.000 description 2
- 108010016219 Acetyl-CoA Carboxylase Proteins 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N Adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 102000003808 Adiponectin Receptors Human genes 0.000 description 2
- 108090000179 Adiponectin Receptors Proteins 0.000 description 2
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N Ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GWYCUGNELBEOMH-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1CC(C1)(F)C=1C(=NC=C(C(=O)OC)C=1)OC Chemical compound C(C1=CC=CC=C1)OC1CC(C1)(F)C=1C(=NC=C(C(=O)OC)C=1)OC GWYCUGNELBEOMH-UHFFFAOYSA-N 0.000 description 2
- LZBKYXCKYXFBME-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C(=O)O)C=1)OC Chemical compound C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C(=O)O)C=1)OC LZBKYXCKYXFBME-UHFFFAOYSA-N 0.000 description 2
- UWJZUIBYIXLSMG-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C(=O)OC)C=1)OC Chemical compound C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C(=O)OC)C=1)OC UWJZUIBYIXLSMG-UHFFFAOYSA-N 0.000 description 2
- QTSVRBDKWZDDQQ-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C=1)CO[Si](C)(C)C(C)(C)C)OC Chemical compound C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C=1)CO[Si](C)(C)C(C)(C)C)OC QTSVRBDKWZDDQQ-UHFFFAOYSA-N 0.000 description 2
- UXMKQLWKOCDZSP-UHFFFAOYSA-N C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1)F)F)C(=O)OCC Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1)F)F)C(=O)OCC UXMKQLWKOCDZSP-UHFFFAOYSA-N 0.000 description 2
- VKDAAIPXQUQNME-UHFFFAOYSA-N C1(CC1)C=1C=NN(C=1CO)C1=C(C=C(C=C1Cl)F)Cl Chemical compound C1(CC1)C=1C=NN(C=1CO)C1=C(C=C(C=C1Cl)F)Cl VKDAAIPXQUQNME-UHFFFAOYSA-N 0.000 description 2
- 101700074178 CCL11 Proteins 0.000 description 2
- 102100019487 CCL11 Human genes 0.000 description 2
- 101700070842 CCR3 Proteins 0.000 description 2
- 102100005861 CCR3 Human genes 0.000 description 2
- 101700043583 CCR5 Proteins 0.000 description 2
- 102100012080 CCR5 Human genes 0.000 description 2
- PAOANWZGLPPROA-RQXXJAGISA-N CGS-21680 Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC(NCCC=3C=CC(CCC(O)=O)=CC=3)=NC(N)=C2N=C1 PAOANWZGLPPROA-RQXXJAGISA-N 0.000 description 2
- JTGSTSYLLQZYQO-UHFFFAOYSA-N COC1=NC=C(C(=O)OC)C=C1C1CC(C1)=O Chemical compound COC1=NC=C(C(=O)OC)C=C1C1CC(C1)=O JTGSTSYLLQZYQO-UHFFFAOYSA-N 0.000 description 2
- 102000005600 Cathepsins Human genes 0.000 description 2
- 108010084457 Cathepsins Proteins 0.000 description 2
- 229950011033 Cenicriviroc Drugs 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- RUDATBOHQWOJDD-BSWAIDMHSA-N Chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 2
- KTJWDVHKAIQDAR-UHFFFAOYSA-N ClC1=C(C(=CC(=C1)F)Cl)C1=NOC(=C1CO)C Chemical compound ClC1=C(C(=CC(=C1)F)Cl)C1=NOC(=C1CO)C KTJWDVHKAIQDAR-UHFFFAOYSA-N 0.000 description 2
- ZAQTWMCACRKTJY-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O ZAQTWMCACRKTJY-UHFFFAOYSA-N 0.000 description 2
- QMAOOOLIUPIGMP-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CNC1)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CNC1)O QMAOOOLIUPIGMP-UHFFFAOYSA-N 0.000 description 2
- 230000037242 Cmax Effects 0.000 description 2
- 229950005980 Cobiprostone Drugs 0.000 description 2
- 241000565118 Cordylophora caspia Species 0.000 description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N Cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 2
- 229940119025 Cysteamine Drugs 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 102100007858 DGAT2 Human genes 0.000 description 2
- 101700003156 DGAT2 Proteins 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 2
- 101700057458 Drice Proteins 0.000 description 2
- 102100016621 ENPP2 Human genes 0.000 description 2
- 101700057276 ENPP2 Proteins 0.000 description 2
- 229950001279 Elafibranor Drugs 0.000 description 2
- 229950000234 Emricasan Drugs 0.000 description 2
- GBXSMTUPTTWBMN-XIRDDKMYSA-N Enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 2
- 229960000873 Enalapril Drugs 0.000 description 2
- 108010061435 Enalapril Proteins 0.000 description 2
- 229940088598 Enzyme Drugs 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229950006535 Ertugliflozin Drugs 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102100008329 FASN Human genes 0.000 description 2
- 101710008102 FASN Proteins 0.000 description 2
- 101700003482 Fgf15 Proteins 0.000 description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 2
- 102000018233 Fibroblast growth factor family Human genes 0.000 description 2
- 108050007372 Fibroblast growth factor family Proteins 0.000 description 2
- 108090000045 G-protein coupled receptors Proteins 0.000 description 2
- 101710042219 GAL6 Proteins 0.000 description 2
- 108010001517 Galectin 3 Proteins 0.000 description 2
- 206010017943 Gastrointestinal conditions Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 229960002743 Glutamine Drugs 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229940096919 Glycogen Drugs 0.000 description 2
- BYSGBSNPRWKUQH-UJDJLXLFSA-N Glycogen Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](O)[C@@H](O[C@@H]2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)O1 BYSGBSNPRWKUQH-UJDJLXLFSA-N 0.000 description 2
- 229920002527 Glycogen Polymers 0.000 description 2
- 102100013175 HCAR2 Human genes 0.000 description 2
- 230000036499 Half live Effects 0.000 description 2
- 210000000987 Immune System Anatomy 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 210000003734 Kidney Anatomy 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 102100011540 LGALS3 Human genes 0.000 description 2
- 102100015591 LOXL2 Human genes 0.000 description 2
- 101700013321 LOXL2 Proteins 0.000 description 2
- 102100011688 LPL Human genes 0.000 description 2
- 229960002397 Linagliptin Drugs 0.000 description 2
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 2
- 102000017055 Lipoprotein lipase Human genes 0.000 description 2
- 108010013563 Lipoprotein lipase Proteins 0.000 description 2
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 2
- 108010019598 Liraglutide Proteins 0.000 description 2
- 102100003430 MAP3K7 Human genes 0.000 description 2
- XJHXZGHPCAKRFK-UHFFFAOYSA-N MBX-8025 Chemical compound CC1=NN(C=2C=CC(=CC=2)C(F)(F)F)N=C1CSC1=CC=C(OCC(O)=O)C(C)=C1 XJHXZGHPCAKRFK-UHFFFAOYSA-N 0.000 description 2
- 102100014726 MECP2 Human genes 0.000 description 2
- 108010093662 Member 11 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 2
- 229960003151 Mercaptamine Drugs 0.000 description 2
- 230000036650 Metabolic stability Effects 0.000 description 2
- 108010072388 Methyl-CpG-Binding Protein 2 Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 210000001853 Microsomes, Liver Anatomy 0.000 description 2
- 102000004233 Multidrug resistance protein 3 Human genes 0.000 description 2
- 108090000743 Multidrug resistance protein 3 Proteins 0.000 description 2
- 102000015528 Myelin Basic Protein Human genes 0.000 description 2
- 108010025255 Myelin Basic Protein Proteins 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- SVCQIVUYSQKNAZ-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methylidene]hydroxylamine Chemical compound ON=CC1=CC=C(F)C=C1F SVCQIVUYSQKNAZ-UHFFFAOYSA-N 0.000 description 2
- 102100016102 NTRK1 Human genes 0.000 description 2
- 101700043017 NTRK1 Proteins 0.000 description 2
- XJLXINKUBYWONI-NNYOXOHSSA-N Nicotinamide adenine dinucleotide phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 2
- 108070000019 Nicotinic acid receptor Proteins 0.000 description 2
- 108009000118 Nuclear Receptors Proteins 0.000 description 2
- 102000007399 Nuclear hormone receptors Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptors Proteins 0.000 description 2
- KKJHWUSOUMFUPD-UHFFFAOYSA-N OC1CC(C1)C=1C(=NC=C(C(=O)OC)C=1)OC Chemical compound OC1CC(C1)C=1C(=NC=C(C(=O)OC)C=1)OC KKJHWUSOUMFUPD-UHFFFAOYSA-N 0.000 description 2
- 229960001601 Obeticholic acid Drugs 0.000 description 2
- QNTASHOAVRSLMD-FCARAQADSA-N Olesoxime Chemical compound C1CC2=C\C(=N/O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 QNTASHOAVRSLMD-FCARAQADSA-N 0.000 description 2
- 229950001051 Olesoxime Drugs 0.000 description 2
- 239000012124 Opti-MEM Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 102000017491 P2Y13 purinoceptor Human genes 0.000 description 2
- 108050005708 P2Y13 purinoceptor Proteins 0.000 description 2
- 108010070503 PAR-2 Receptor Proteins 0.000 description 2
- 108091007929 PDGF receptors Proteins 0.000 description 2
- 206010062585 Peripheral arterial occlusive disease Diseases 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N Pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 229960005095 Pioglitazone Drugs 0.000 description 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N Pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 229920002873 Polyethylenimine Polymers 0.000 description 2
- 206010061529 Polyp Diseases 0.000 description 2
- 229960002965 Pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N Pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 229950002828 Propagermanium Drugs 0.000 description 2
- 102000018402 Protease-activated receptor 2 Human genes 0.000 description 2
- 108060006633 Protein Kinases Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O Pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- XEABSBMNTNXEJM-UHFFFAOYSA-N Repagermanium Chemical compound OC(=O)CC[Ge](=O)O[Ge](=O)CCC(O)=O XEABSBMNTNXEJM-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 101710026013 SPCC1281.06c Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229950006544 Saroglitazar Drugs 0.000 description 2
- DLSWIYLPEUIQAV-CCUURXOWSA-N Semaglutide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CC[C@@H](NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)C(C)(C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DLSWIYLPEUIQAV-CCUURXOWSA-N 0.000 description 2
- 229950011186 Semaglutide Drugs 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 229950009513 Simtuzumab Drugs 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N Simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 229940083599 Sodium Iodide Drugs 0.000 description 2
- 229940054269 Sodium Pyruvate Drugs 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229950005268 Sotagliflozin Drugs 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 101710028316 T16G12.1 Proteins 0.000 description 2
- 102100008847 THRB Human genes 0.000 description 2
- 102100012087 TLR4 Human genes 0.000 description 2
- 101700022711 TLR4 Proteins 0.000 description 2
- 108010071769 Thyroid Hormone Receptors beta Proteins 0.000 description 2
- 101700066517 VAP-1 Proteins 0.000 description 2
- 229940029983 VITAMINS Drugs 0.000 description 2
- 229940021016 Vitamin IV solution additives Drugs 0.000 description 2
- ZBZYAGHPYBNFDY-UHFFFAOYSA-N [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CN(C1)C=1C=C(C#N)C=CN=1)O)Cl Chemical compound [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CN(C1)C=1C=C(C#N)C=CN=1)O)Cl ZBZYAGHPYBNFDY-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000001270 agonistic Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229950006993 alipogene tiparvovec Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 108091005508 amylin receptors Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000002202 anti-cholestatic Effects 0.000 description 2
- 230000003510 anti-fibrotic Effects 0.000 description 2
- 101710043150 apeII Proteins 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- 229960005370 atorvastatin Drugs 0.000 description 2
- UQUPQEUNHVVNKW-UHFFFAOYSA-N azetidin-1-ium-3-ol;chloride Chemical compound Cl.OC1CNC1 UQUPQEUNHVVNKW-UHFFFAOYSA-N 0.000 description 2
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000975 bioactive Effects 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 230000005591 charge neutralization Effects 0.000 description 2
- 239000003467 chloride channel stimulating agent Substances 0.000 description 2
- 230000001989 choleretic Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 229960003834 dapagliflozin Drugs 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000000378 dietary Effects 0.000 description 2
- 235000013367 dietary fats Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000036267 drug metabolism Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- UAOCLDQAQNNEAX-ABMICEGHSA-N ethyl [(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[5-methyl-1-propan-2-yl-4-[(4-propan-2-yloxyphenyl)methyl]pyrazol-3-yl]oxyoxan-2-yl]methyl carbonate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)OCC)O[C@H]1OC1=NN(C(C)C)C(C)=C1CC1=CC=C(OC(C)C)C=C1 UAOCLDQAQNNEAX-ABMICEGHSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229960003765 fluvastatin Drugs 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002068 genetic Effects 0.000 description 2
- 230000004110 gluconeogenesis Effects 0.000 description 2
- 150000008134 glucuronides Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 230000001976 improved Effects 0.000 description 2
- 230000002757 inflammatory Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 229950000991 ipragliflozin Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000000155 isotopic Effects 0.000 description 2
- 150000002545 isoxazoles Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- YSDQQAXHVYUZIW-QCIJIYAXSA-N liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 2
- 229960002701 liraglutide Drugs 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002503 metabolic Effects 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000002438 mitochondrial Effects 0.000 description 2
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000003287 optical Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108091011479 pegilodecakin Proteins 0.000 description 2
- 229950007092 pegilodecakin Drugs 0.000 description 2
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 229960002797 pitavastatin Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- RZVOGBCISVYZAK-CMTWHQOSSA-M potassium;[(2R,3R,4S,5R,6R)-6-[[3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-4-hydroxy-1,1-dioxo-4,5-dihydro-2H-1$l^{6}-benzothiepin-5-yl]phenyl]carbamoylamino]-3,5-dihydroxy-4-phenylmethoxyoxan-2-yl]methyl sulfate;ethanol;hydrate Chemical compound O.[K+].CCO.O([C@H]1[C@H](O)[C@@H](COS([O-])(=O)=O)O[C@H]([C@@H]1O)NC(=O)NC=1C=CC=C(C=1)[C@@H]1C2=CC(=CC=C2S(=O)(=O)C[C@@]([C@@H]1O)(CC)CCCC)N(C)C)CC1=CC=CC=C1 RZVOGBCISVYZAK-CMTWHQOSSA-M 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 230000000750 progressive Effects 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 230000002685 pulmonary Effects 0.000 description 2
- 239000003227 purinergic agonist Substances 0.000 description 2
- 150000003217 pyrazoles Chemical group 0.000 description 2
- 230000002285 radioactive Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229950011516 remogliflozin etabonate Drugs 0.000 description 2
- 230000000754 repressing Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 101700066061 scd1 Proteins 0.000 description 2
- 108010060325 semaglutide Proteins 0.000 description 2
- 231100000489 sensitizer Toxicity 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 229960003310 sildenafil Drugs 0.000 description 2
- 108010074113 simtuzumab Proteins 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 108010003524 sodium-bile acid cotransporter Proteins 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin dichloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical Effects 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229930003231 vitamins Natural products 0.000 description 2
- IXXFZUPTQVDPPK-ZAWHAJPISA-N (1R,2R,4R,6R,7R,8R,10S,13R,14S)-17-[4-[4-(3-aminophenyl)triazol-1-yl]butyl]-7-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-13-ethyl-10-fluoro-6-methoxy-2,4,6,8,10,14-hexamethyl-12,15-dioxa-17-azabicyclo[12.3.0]heptadecane-3,9,11,16-tet Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@](C)(F)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3N=NC(=C3)C=3C=C(N)C=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O IXXFZUPTQVDPPK-ZAWHAJPISA-N 0.000 description 1
- GOBWNIHKINSIII-UHFFFAOYSA-N (2,6-dichloro-4-fluorophenyl)hydrazine;hydrochloride Chemical compound Cl.NNC1=C(Cl)C=C(F)C=C1Cl GOBWNIHKINSIII-UHFFFAOYSA-N 0.000 description 1
- NPBCMXATLRCCLF-IRRLEISYSA-N (2S,4R)-4-[(3R,5S,6R,7R,8R,9S,10S,12S,13R,14S,17R)-6-ethyl-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 NPBCMXATLRCCLF-IRRLEISYSA-N 0.000 description 1
- QYYDXDSPYPOWRO-JHMCBHKWSA-N (3R)-3-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]butanoic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CC(O)=O)C)[C@@]2(C)CC1 QYYDXDSPYPOWRO-JHMCBHKWSA-N 0.000 description 1
- LCDDAGSJHKEABN-MLGOLLRUSA-N (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-[(2-methylpropan-2-yl)oxymethyl]piperazin-2-one Chemical compound C1CNC(=O)[C@@H](COC(C)(C)C)N1C(=O)C[C@H](N)CC1=CC(F)=C(F)C=C1F LCDDAGSJHKEABN-MLGOLLRUSA-N 0.000 description 1
- SHKXZIQNFMOPBS-OOMQYRRCSA-N (4R)-4-[(3S,5S,7R,8R,9S,10S,12S,13R,14S,17R)-7,12-dihydroxy-3-(icosanoylamino)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound O[C@H]1C[C@@H]2[C@@]3(C)CC[C@H](NC(=O)CCCCCCCCCCCCCCCCCCC)C[C@H]3C[C@@H](O)[C@H]2[C@@H]2CC[C@H]([C@H](C)CCC(O)=O)[C@]21C SHKXZIQNFMOPBS-OOMQYRRCSA-N 0.000 description 1
- 125000005926 1,2-dimethylbutyloxy group Chemical group 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 1
- GQBRZBHEPUQRPL-LJQANCHMSA-N 1-[4-[4-[3-methyl-4-[[(1R)-1-phenylethoxy]carbonylamino]-1,2-oxazol-5-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound O([C@H](C)C=1C=CC=CC=1)C(=O)NC=1C(C)=NOC=1C(C=C1)=CC=C1C(C=C1)=CC=C1C1(C(O)=O)CC1 GQBRZBHEPUQRPL-LJQANCHMSA-N 0.000 description 1
- WCGPCBACLBHDCI-UHFFFAOYSA-N 2,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(F)=C1 WCGPCBACLBHDCI-UHFFFAOYSA-N 0.000 description 1
- YAUYKCFMKMZTEX-UHFFFAOYSA-N 2,6-dichloro-4-fluoroaniline Chemical compound NC1=C(Cl)C=C(F)C=C1Cl YAUYKCFMKMZTEX-UHFFFAOYSA-N 0.000 description 1
- NXOLVMFMAFCDSR-UHFFFAOYSA-M 2-(chloromethyl)oxirane;prop-2-en-1-amine;N-prop-2-enyldecan-1-amine;trimethyl-[6-(prop-2-enylamino)hexyl]azanium;chloride Chemical compound [Cl-].NCC=C.ClCC1CO1.CCCCCCCCCCNCC=C.C[N+](C)(C)CCCCCCNCC=C NXOLVMFMAFCDSR-UHFFFAOYSA-M 0.000 description 1
- BGDYLOGCMJAUHR-UHFFFAOYSA-N 2-chloro-3-fluoro-6-methylpyridine Chemical compound CC1=CC=C(F)C(Cl)=N1 BGDYLOGCMJAUHR-UHFFFAOYSA-N 0.000 description 1
- QRXBTPFMCTXCRD-UHFFFAOYSA-N 2-chloropyridine-4-carbonitrile Chemical compound ClC1=CC(C#N)=CC=N1 QRXBTPFMCTXCRD-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-M 3-hydroxybutyrate Chemical compound CC(O)CC([O-])=O WHBMMWSBFZVSSR-UHFFFAOYSA-M 0.000 description 1
- GPPSQLLIFNWNSB-UHFFFAOYSA-N 3-phenylmethoxycyclobutan-1-one Chemical compound C1C(=O)CC1OCC1=CC=CC=C1 GPPSQLLIFNWNSB-UHFFFAOYSA-N 0.000 description 1
- SDMBRCRVFFHJKR-UHFFFAOYSA-N 6-(5-carboxy-5-methylhexoxy)-2,2-dimethylhexanoic acid Chemical compound OC(=O)C(C)(C)CCCCOCCCCC(C)(C)C(O)=O SDMBRCRVFFHJKR-UHFFFAOYSA-N 0.000 description 1
- 102100014002 ABCB4 Human genes 0.000 description 1
- 101700085131 ABCB4 Proteins 0.000 description 1
- 102100006348 ABCC4 Human genes 0.000 description 1
- 101710024119 ABCC4 Proteins 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- 102100001248 AKT1 Human genes 0.000 description 1
- 101700006234 AKT1 Proteins 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 101700024603 ANNU Proteins 0.000 description 1
- 101700012456 AOC2 Proteins 0.000 description 1
- 102000005416 ATP-Binding Cassette Transporters Human genes 0.000 description 1
- 108010006533 ATP-Binding Cassette Transporters Proteins 0.000 description 1
- 102100012868 ATP8B1 Human genes 0.000 description 1
- 101710012000 ATP8B1 Proteins 0.000 description 1
- 230000035533 AUC Effects 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- 210000004100 Adrenal Glands Anatomy 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- 206010001897 Alzheimer's disease Diseases 0.000 description 1
- 102000013918 Apolipoproteins E Human genes 0.000 description 1
- 108010025628 Apolipoproteins E Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229940090047 Auto-Injector Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- GVOJXCKEOHYNCQ-UHFFFAOYSA-N BrC1=C(C=C(OCC=2C(=NOC=2C2CC2)C2=C(C=C(C=C2Cl)F)Cl)C=C1)Cl Chemical compound BrC1=C(C=C(OCC=2C(=NOC=2C2CC2)C2=C(C=C(C=C2Cl)F)Cl)C=C1)Cl GVOJXCKEOHYNCQ-UHFFFAOYSA-N 0.000 description 1
- KWBVCYRDBSDHKL-UHFFFAOYSA-N BrC=1C(=NC=C(C=1)CO[Si](C)(C)C(C)(C)C)OC Chemical compound BrC=1C(=NC=C(C=1)CO[Si](C)(C)C(C)(C)C)OC KWBVCYRDBSDHKL-UHFFFAOYSA-N 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- CRTHBSPQSAMNNV-UHFFFAOYSA-N C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C=1)CO)OC Chemical compound C(C1=CC=CC=C1)OC1CC(C1)(O)C=1C(=NC=C(C=1)CO)OC CRTHBSPQSAMNNV-UHFFFAOYSA-N 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- ZVQKONMNEMUVHU-UHFFFAOYSA-N C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1)F)F)CO Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1)F)F)CO ZVQKONMNEMUVHU-UHFFFAOYSA-N 0.000 description 1
- 102100017603 CALCR Human genes 0.000 description 1
- 101700053901 CD248 Proteins 0.000 description 1
- 102100000196 CD248 Human genes 0.000 description 1
- 101700046984 CDK20 Proteins 0.000 description 1
- 102100018442 CYP7A1 Human genes 0.000 description 1
- 101710008851 CYP7A1 Proteins 0.000 description 1
- 102400000113 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 229960004015 Calcitonin Drugs 0.000 description 1
- 108010001789 Calcitonin Receptors Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 102000003727 Caveolin-1 Human genes 0.000 description 1
- 108090000026 Caveolin-1 Proteins 0.000 description 1
- 101700010311 Ccl9 Proteins 0.000 description 1
- 210000003483 Chromatin Anatomy 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- PSGCVPPFLGGTOH-UHFFFAOYSA-N ClC1=C(C=CC(=C1)O)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)O)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O PSGCVPPFLGGTOH-UHFFFAOYSA-N 0.000 description 1
- ZVNNLRILRFAEFR-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC1=C(C=NN1C1=C(C=C(C=C1Cl)F)Cl)C1CC1)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC1=C(C=NN1C1=C(C=C(C=C1Cl)F)Cl)C1CC1)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O ZVNNLRILRFAEFR-UHFFFAOYSA-N 0.000 description 1
- MMKZGOIJUWWGKD-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CC(C1)C=1C(=NC=C(C(=O)OC)C=1)OC)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CC(C1)C=1C(=NC=C(C(=O)OC)C=1)OC)O MMKZGOIJUWWGKD-UHFFFAOYSA-N 0.000 description 1
- IZZQEWILURCKKE-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)NCC(=O)OC)C=C1F)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C1=NC=C(C(=O)NCC(=O)OC)C=C1F)O IZZQEWILURCKKE-UHFFFAOYSA-N 0.000 description 1
- IKHZPOPALSWEGF-UHFFFAOYSA-N ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C=1C=C(C(=O)OC)C=CN=1)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C=1C=C(C(=O)OC)C=CN=1)O IKHZPOPALSWEGF-UHFFFAOYSA-N 0.000 description 1
- SFCGDTAPGSSNDN-UHFFFAOYSA-M ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C=1C=C(C(=O)[O-])C=CN=1)O Chemical compound ClC1=C(C=CC(=C1)OCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1Cl)F)Cl)C1(CN(C1)C=1C=C(C(=O)[O-])C=CN=1)O SFCGDTAPGSSNDN-UHFFFAOYSA-M 0.000 description 1
- SSGWKWPYRNDDIG-UHFFFAOYSA-N ClCC1=C(C=NN1C1=C(C=C(C=C1Cl)F)Cl)C1CC1 Chemical compound ClCC1=C(C=NN1C1=C(C=C(C=C1Cl)F)Cl)C1CC1 SSGWKWPYRNDDIG-UHFFFAOYSA-N 0.000 description 1
- AXWVEEQUHNZQSY-UHFFFAOYSA-N ClCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1)F)F Chemical compound ClCC=1C(=NOC=1C1CC1)C1=C(C=C(C=C1)F)F AXWVEEQUHNZQSY-UHFFFAOYSA-N 0.000 description 1
- 230000037250 Clearance Effects 0.000 description 1
- 229920002905 Colesevelam Polymers 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920002676 Complementary DNA Polymers 0.000 description 1
- 102000008954 Copper amine oxidase Human genes 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 201000008260 Crohn's colitis Diseases 0.000 description 1
- 108050006400 Cyclins Proteins 0.000 description 1
- 102000016736 Cyclins Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 210000000172 Cytosol Anatomy 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N DCM Dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 102100007851 DGAT1 Human genes 0.000 description 1
- 101700039623 DGAT1 Proteins 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N DMSO dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Dichlothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102000016354 EC 2.4.1.17 Human genes 0.000 description 1
- 108010092364 EC 2.4.1.17 Proteins 0.000 description 1
- 102100004921 EDN1 Human genes 0.000 description 1
- 102100016692 ESR1 Human genes 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N Endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 108010072834 Endothelin-1 Proteins 0.000 description 1
- 241000305071 Enterobacterales Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241001198387 Escherichia coli BL21(DE3) Species 0.000 description 1
- 210000003238 Esophagus Anatomy 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N Ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N Ethyl eicosapentaenoic acid Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 1
- 229950011259 Evogliptin Drugs 0.000 description 1
- 206010061127 Eye degenerative disease Diseases 0.000 description 1
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108060003095 GAS2 Proteins 0.000 description 1
- 102000025873 GPCR, family 2, glucagon receptor Human genes 0.000 description 1
- 108010063919 GPCR, family 2, glucagon receptor Proteins 0.000 description 1
- 229950004781 Gemcabene Drugs 0.000 description 1
- 206010061989 Glomerulosclerosis Diseases 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 229940097043 Glucuronic Acid Drugs 0.000 description 1
- 240000001340 Gmelina philippensis Species 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 208000002672 Hepatitis B Diseases 0.000 description 1
- 108009000423 Hepatitis B infection Proteins 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000009576 Hypercholesterolemia Diseases 0.000 description 1
- 208000006575 Hypertriglyceridemia Diseases 0.000 description 1
- 208000001024 Intrahepatic Cholestasis Diseases 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N Irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 101700016050 JAK2 Proteins 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- XXYGTCZJJLTAGH-UHFFFAOYSA-N LGK974 Chemical compound C1=NC(C)=CC(C=2C(=CC(CC(=O)NC=3N=CC(=CC=3)C=3N=CC=NC=3)=CN=2)C)=C1 XXYGTCZJJLTAGH-UHFFFAOYSA-N 0.000 description 1
- 101710010130 LTP12 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108010029223 MAP kinase kinase kinase 7 Proteins 0.000 description 1
- 101710039102 MAP3K5 Proteins 0.000 description 1
- 102100003436 MAP3K5 Human genes 0.000 description 1
- 101710039067 MAP3K8 Proteins 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 102000000424 Matrix Metalloproteinase 2 Human genes 0.000 description 1
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N MeOH methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 208000008466 Metabolic Disease Diseases 0.000 description 1
- 230000035633 Metabolized Effects 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- 229960003105 Metformin Drugs 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010082699 NADPH Oxidase 4 Proteins 0.000 description 1
- 102000004722 NADPH Oxidases Human genes 0.000 description 1
- 108010002998 NADPH Oxidases Proteins 0.000 description 1
- 102000004019 NADPH oxidase 1 Human genes 0.000 description 1
- 108090000424 NADPH oxidase 1 Proteins 0.000 description 1
- 102100011189 NCOA3 Human genes 0.000 description 1
- 101700068083 NCOA3 Proteins 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N NMP N-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 102100011851 NOX4 Human genes 0.000 description 1
- ACFIXJIJDZMPPO-XCSFTKGKSA-N Nadph Dihydro-Nicotinamide-Adenine-Dinucleotidephosphate Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO[P@](O)(=O)O[P@@](O)(=O)OC[C@H]2[C@@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-XCSFTKGKSA-N 0.000 description 1
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N Nicotinamide adenine dinucleotide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- 229920001850 Nucleic acid sequence Polymers 0.000 description 1
- 229940100692 Oral Suspension Drugs 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 102220396602 PET117 C57L Human genes 0.000 description 1
- 102100003779 PLTP Human genes 0.000 description 1
- 101700031669 PLTP Proteins 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102000024367 PPAR alpha Human genes 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 210000001428 Peripheral Nervous System Anatomy 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 108091000081 Phosphotransferases Proteins 0.000 description 1
- 241000254064 Photinus pyralis Species 0.000 description 1
- 229960003073 Pirfenidone Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N Pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000242739 Renilla Species 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N Rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 101700033344 SCP2 Proteins 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 Saccharin Drugs 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 108050002485 Sirtuins Proteins 0.000 description 1
- 102000011990 Sirtuins Human genes 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M Sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229950008588 Solithromycin Drugs 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N Sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 101700034322 TGAS Proteins 0.000 description 1
- 101710009979 TSW12 Proteins 0.000 description 1
- NQSIKKSFBQCBSI-UHFFFAOYSA-N Tetrapropylammonium perruthenate Chemical compound [O-][Ru](=O)(=O)=O.CCC[N+](CCC)(CCC)CCC NQSIKKSFBQCBSI-UHFFFAOYSA-N 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N Tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000036335 Tissue distribution Effects 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- SHGAZHPCJJPHSC-NWVFGJFESA-N Tretinoin Chemical compound OC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NWVFGJFESA-N 0.000 description 1
- 229960001727 Tretinoin Drugs 0.000 description 1
- DRTQHJPVMGBUCF-UCVXFZOQSA-N Uridine Natural products O[C@H]1[C@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UCVXFZOQSA-N 0.000 description 1
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 1
- 229940045145 Uridine Drugs 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N Ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 Ursodiol Drugs 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N Vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
- 229940046008 Vitamin D Drugs 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 101710010141 WAX9A Proteins 0.000 description 1
- 101710010143 WAX9B Proteins 0.000 description 1
- CWTUREABAILGIK-UHFFFAOYSA-L [Li+].[Cl-].[Cl-].CC(C)[Mg+] Chemical compound [Li+].[Cl-].[Cl-].CC(C)[Mg+] CWTUREABAILGIK-UHFFFAOYSA-L 0.000 description 1
- QYAJNLIFLCJYNY-UHFFFAOYSA-M [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CN(C1)C(=O)[O-])O)Cl Chemical compound [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CN(C1)C(=O)[O-])O)Cl QYAJNLIFLCJYNY-UHFFFAOYSA-M 0.000 description 1
- UKBHGBHCKGQCHR-UHFFFAOYSA-N [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O)Cl Chemical compound [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CN(C1)C1=NC=C(C(=O)OC)C=C1F)O)Cl UKBHGBHCKGQCHR-UHFFFAOYSA-N 0.000 description 1
- UTQCHRYALQNQDS-UHFFFAOYSA-N [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CNC1)O)Cl Chemical compound [Si](C)(C)(C(C)(C)C)OC1=CC(=C(C=C1)C1(CNC1)O)Cl UTQCHRYALQNQDS-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940121373 acetyl-CoA carboxylase inhibitors Drugs 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000002730 additional Effects 0.000 description 1
- 239000002593 adenosine A3 receptor agonist Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000879 anti-atherosclerotic Effects 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 230000000118 anti-eoplastic Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000038129 antigens Human genes 0.000 description 1
- 108091007172 antigens Proteins 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000000386 athletic Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229950010582 betaine anhydrous Drugs 0.000 description 1
- 102000030806 bile acid binding proteins Human genes 0.000 description 1
- 108091022019 bile acid binding proteins Proteins 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003293 cardioprotective Effects 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000003907 chenodeoxycholic acid group Chemical group 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000012085 chronic inflammatory response Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000035512 clearance Effects 0.000 description 1
- 230000003081 coactivator Effects 0.000 description 1
- 229960001152 colesevelam Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000012969 defense response to bacterium Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 239000000841 delta opiate receptor agonist Substances 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide DMF Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 230000003467 diminishing Effects 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- XGZRAKBCYZIBKP-UHFFFAOYSA-L disodium;dihydroxide Chemical compound [OH-].[OH-].[Na+].[Na+] XGZRAKBCYZIBKP-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion media Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000013931 endocrine signaling Effects 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- NEEXXQDCFONWJB-UHFFFAOYSA-N ethyl 3-cyclopropyl-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CC1CC1 NEEXXQDCFONWJB-UHFFFAOYSA-N 0.000 description 1
- LFSVADABIDBSBV-UHFFFAOYSA-N ethyl 3-cyclopropyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1CC1 LFSVADABIDBSBV-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 239000006277 exogenous ligand Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000010230 functional analysis Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000036433 growing body Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000004024 hepatic stellate cells Anatomy 0.000 description 1
- 108010032844 hepatitis C virus NS3 protein Proteins 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001771 impaired Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000004155 insulin signaling pathway Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000027634 intracellular receptors Human genes 0.000 description 1
- 108091007905 intracellular receptors Proteins 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000005445 isotope effect Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 108010053156 lipid transfer protein Proteins 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 1
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- MULLTHQTADMZDM-UHFFFAOYSA-N methyl 2-bromopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(Br)=C1 MULLTHQTADMZDM-UHFFFAOYSA-N 0.000 description 1
- UCOBYBCUAQNLBK-UHFFFAOYSA-N methyl 5-bromo-6-methoxypyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OC)C(Br)=C1 UCOBYBCUAQNLBK-UHFFFAOYSA-N 0.000 description 1
- PXHKAVXJQLVUBI-UHFFFAOYSA-N methyl 6-bromo-5-fluoropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(Br)C(F)=C1 PXHKAVXJQLVUBI-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000003228 microsomal Effects 0.000 description 1
- 239000006956 minimum essential medium Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000002552 multiple reaction monitoring Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000002107 myocardial Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000010397 one-hybrid screening Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000014306 paracrine signaling Effects 0.000 description 1
- 230000003071 parasitic Effects 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 108060002037 pde-3 Proteins 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 230000000858 peroxisomal Effects 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000003371 phospholipase C inhibitor Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229940096701 plain lipid modifying drugs HMG CoA reductase inhibitors Drugs 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 108010065251 protein kinase modulator Proteins 0.000 description 1
- 239000003379 purinergic P1 receptor agonist Substances 0.000 description 1
- 239000003247 radioactive fallout Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001172 regenerating Effects 0.000 description 1
- 238000003571 reporter gene assay Methods 0.000 description 1
- 230000000284 resting Effects 0.000 description 1
- 102000034577 retinoid X receptors Human genes 0.000 description 1
- 108010038912 retinoid X receptors Proteins 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000001235 sensitizing Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 108091008059 testicular receptors 4 Proteins 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 101700012968 tgl Proteins 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000035916 transactivation Effects 0.000 description 1
- 230000002103 transcriptional Effects 0.000 description 1
- 108091006090 transcriptional activators Proteins 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 229940115889 ursodeoxycholic acid Drugs 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
Abstract
The present disclosure relates generally to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.
Description
FXR (NR1H4) MODULATING COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefît of US Provisional App. No. 62/349,490, filed June 13, 2016, the entirety of which is hereby incorporated by reference.
SEQUENCE LISTING
[0002] The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the spécification. The name of the text file containing the Sequence Listing is 1165_PF_ST25.txt. The text file created on May 16, 2017, is about 550 bytes and submitted électronically via EFS-Web.
FIELD
[0003] The présent disclosure relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.
BACKGROUND
[0004] Multicellular organisms are dépendent on advanced mechanisms of information transfer between cells and body compartments. The information that is transmitted can be highly complex and can resuit in the alteration of genetic programs involved in cellular différentiation, prolifération, or reproduction. The signais, or hormones, are often low molecular weight molécules, such as peptides, fatty acid, or cholestérol dérivatives.
[0005] Many of these signais produce their effects by ultimately changing the transcription of spécifie genes. One well-studied group of proteins that médiate a cell’s response to a variety of signais is the family of transcription factors known as nuclear receptors, hereinafter referred to often as “NR.” Members of this group include receptors for steroid hormones, vitamin D, eedysone, cis and trans retinoic acid, thyroid hormone, bile acids, cholesterol-derivatives, fatty acids (and other peroxisomal proliferators), as well as so-called orphan receptors, proteins that are structurally similar to other members of this group, but for which no ligands are known. Orphan receptors may be indicative of unknown signalling pathways in the cell or may be nuclear receptors that function without ligand activation. The activation of transcription by some of these orphan receptors may occur in the absence of an exogenous ligand and/or through signal transduction pathways originating from the cell surface.
[0006] In general, three functional domains hâve been defined in NRs. An amino terminal domain is believed to hâve some regulatory function. It is followed by a DNA-binding domain (hereinafter referred to as “DBD”), which usually comprises two zinc finger éléments and recognizes a spécifie Hormone Responsive Element (hereinafter referred to as “HRE”) within the promoters of responsive genes. Spécifie amino acid residues in the “DBD” hâve been shown to confer DNA sequence binding specificity. A ligand-binding-domain (hereinafter referred to as “LBD”) is at the carboxy-terminal région of known NRs.
[0007] In the absence of hormone, the LBD appears to interfère with the interaction of the DBD with its HRE. Hormone binding seems to resuit in a conformational change in the NR and thus opens this interférence. A NR without the LBD constitutively activâtes transcription but at a low level.
[0008] Coactivators or transcriptional activators are proposed to bridge between sequence spécifie transcription factors, and the basal transcription machinery and in addition to influence the chromatin structure of a target cell. Several proteins like SRC-1, ACTR, and Gripl interact with NRs in a ligand enhanced manner.
[0009] Nuclear receptor modulators like steroid hormones affect the growth and function of spécifie cells by binding to intracellular receptors and forming nuclear receptor-ligand complexes. Nuclear receptor-hormone complexes then interact with a HRE in the control région of spécifie genes and alter spécifie gene expression.
[0010] The Famesoid X Receptor alpha (hereinafter also often referred to as NR1H4 when referring to the human receptor) is a prototypical type 2 nuclear receptor which activâtes genes upon binding to a promoter région of target genes in a heterodimeric fashion with Retinoid X Receptor. The relevant physiological ligands of NR1H4 are bile acids. The most potent one is chenodeoxycholic acid (CDCA), which régulâtes the expression of several genes that participate in bile acid homeostasis. Famesol and dérivatives, together called famesoids, are originally described to activate the rat orthologue at high concentration but they do not activate the human or mouse receptor. FXR is expressed in the liver, throughout the entire gastrointestinal tract including the esophagus, stomach, duodénum, small intestine, colon, ovary, adrenal gland and kidney. Beyond controlling intracellular gene expression, FXR seems to be also involved in paracrine and endocrine signalling by upregulating the expression of the cytokine Fibroblast Growth Factor 15 (rodents) or 19 (monkeys, humans A).
[0011] Although numerous FXR agonists are known, there is a need for improved FXR agonists.
SUMMARY
[0012] The présent disclosure provides compounds bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.
[0013] The présent disclosure provides compounds according to Formula (I):
O) wherein:
Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, Ci-4-alkoxy, halo-Ci-4-alkoxy, -CH2F, -CHF2, and -CF3;
Y is N or CH;
A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently selected from halogen, Cwalkoxy, halo-Cwalkoxy, Ci-4-alkyl, and haloCi-4-alkyl;
Z is isoxazole substituted with R1 or pyrazole substituted with R1;
R1 is Ci-4-alkyl or Cs^-cycloalkyl, wherein said Ci-4-alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, Ci-3-alkoxy, and fluoro-Ci-3-alkoxy, and said C3-6-cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, Ci-3-alkyl, fluoro-Ci-3-alkyl, C1-3alkoxy, and fluoro-Ci-3-alkoxy;
R2 and R3 are independently selected from hydrogen, halogen, methoxy, -CF3, -CHF2, CH2F, -OCH2F, -OCHF2, -OCF3, and methyl;
R4 is -CO2R5 or -C(O)NRSR6;
R5 is hydrogen, Ci-6-alkyl, or halo-Cwalkyl; and
R6 is hydrogen or Ci-6-alkyl, wherein said Ci^-alkyl is optionally substituted with 1 to 6 substituents independently selected from halogen, -SO3H, and -CO2H;
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof .
[0014] Some embodiments provide for pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable excipient.
[0015] Also provided herein are methods of treating a patient having an FXR mediated condition comprising administering a compound of formula (I) to a patient in need thereof.
DESCRIPTION OF THE FIGURES
[0016] FIG. 1 : Plasma exposure of Example 3 and Comparative Example 2 versus plasma FGF19 levels in cynomolgus monkey.
[0017] FIG 2: FGF19 levels generated in cynomolgus monkey with increasing oral doses of Example 3 and Comparative Example 2.
DETAILED DESCRIPTION
Définitions
[0018] The following description sets forth exemplary embodiments of the présent technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the présent disclosure but is instead provided as a description of exemplary embodiments.
[0019] As used in the présent spécification, the following words, phrases and symbols are generally intended to hâve the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
[0020] The disclosures illustratively described herein may suitably be practiced in the absence of any element or éléments, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein hâve been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any équivalents of the features shown and described or portions thereof, but it is recognized that varions modifications are possible within the scope of the disclosure claimed.
[0021] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a Chemical group is a matter of convenience; Chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a Chemical group is written or named.
[0022] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “Ci^ alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
[0023] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameterperse. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ±1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictâtes otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and équivalents thereof known to those skilled in the art.
[0024] In the context of the présent disclosure “alkyl” means a saturated hydrocarbon chain, which may be straight chained or branched. In the context of the présent disclosure, “Ci-6-alkyl” means a saturated alkyl chain having 1 to 6 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl, isopentyl, neopentyl and n-hexyl.
[0025] The term “haloalkyl” means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen. A non-limiting example thereof is CF3.
[0026] A “cycloalkyl” group means a saturated or partially unsaturated mono-, bi- or spirocyclic hydrocarbon ring System.
[0027] An “alkoxy” group refers to -O-alkyl, wherein alkyl is as defined herein. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, secbutoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
[0028] “Halogen” or “halo” refers to a F, Cl, Br, or I atom.
[0029] “Hydroxyl” or “hydroxy” refers to -OH.
[0030] “Haloalkoxy” refers to an alkoxy group as defined herein wherein one or more hydrogen atoms in the alkyi chain are replaced by a halogen.
[0031] “Fluoroalkyl” refers to an alkyi group as defined herein wherein one or more hydrogen atoms in the alkyi chain are replaced by fluoro.
[0032] “Fluoroalkoxy” refers to an alkoxy group as defined herein wherein one or more hydrogen atoms in the alkyi chain are replaced by fluoro.
[0033] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
[0034] Furthermore, the compounds of the présent disclosure may be subject to tautomerism. Where tautomerism, e.g. keto-enol tautomerism, of compounds of the présent disclosure or their prodrugs may occur, the individual forms, like e.g. the keto and enol form, are each within the scope of the disclosure as well as their mixtures in any ratio. The same applies for stéréo isomers, like e.g. enantiomers, cis/trans isomers, conformera and the like.
[0035] The term “protecting group” refera to a moiety of a compound that masks or altéra the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired Chemical reactions, e.g., making and breaking Chemical bonds in an ordered and planned fashion. The term “deprotecting” refera to removing the protecting group.
[0036] A “leaving group” includes a molecular fragment that can départ with a pair of électrons from a covalent bond to the reacting carbon atom during a Chemical reaction.
[0037] It will be appreciated by the skilled person that when lists of alternative substituents include members which, because of their valency requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read with the knowledge of the skilled person to include only those members of the list which are suitable for substituting the particular group.
[0038] In some embodiments, the compounds of the présent disclosure can be in the form of a “prodrug.” The term “prodrug” is defined in the pharmaceutical field as a biologically inactive dérivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some Chemical or enzymatic pathway. Examples of prodrugs include esterified carboxylic acids.
[0039] In the human liver, UDP-glucuronosyltransferases act on certain compounds having amino, carbamyl, thio (sulfhydryl) or hydroxyl groups to conjugate uridine diphosphate-a-Dglucuronic acid through glycoside bonds, or to esterify compounds with carboxy or hydroxyl groups in the process of phase Π metabolism. Compounds of the présent disclosure may be glucuronidated, that is to say, conjugated to glucuronic acid, to form glucuronides, particularîy (P-D)glucuronides.
[0040] One step in the formation of bile is the conjugation of the individual bile acids with an amino acid, particularîy glycine or taurine. Compounds of the présent disclosure may be conjugated with glycine or taurine at a substitutable position.
[0041] The compounds of the présent disclosure can be in the form of a pharmaceutically acceptable sait. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the présent disclosure contain one or more acidic or basic groups, the disclosure also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the présent disclosure which contain acidic groups can be présent on these groups and can be used according to the disclosure, for example, as alkali métal salts, alkaline earth métal salts or ammonium salts. More précisé examples of such salts include sodium salts, potassium salts, calcium salts, magnésium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the présent disclosure which contain one or more basic groups, i.e. groups which can be protonated, can be présent and can be used according to the disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, asco±ic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the présent disclosure simultaneously contain acidic and basic groups in the molécule, the disclosure also includes, in addition to the sait forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The présent disclosure also includes ail salts ofthe compounds of the présent disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for Chemical reactions or for the préparation of pharmaceutically acceptable salts.
[0042] Further the compounds of the présent disclosure may be présent in the form of solvatés, such as those which include as solvaté water, or pharmaceutically acceptable solvatés, such as alcohols, in particular éthanol. A “solvaté” is formed by the interaction of a solvent and a compound.
[0043] In certain embodiments, provided are optical isomers, racemates, or other mixtures thereof of the compounds described herein or a pharmaceutically acceptable sait or a mixture thereof If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. In those situations, the single enantiomer or diastereomer, i.e., optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using for example, a chiral high pressure liquid chromatography (HPLC) column.
[0044] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The présent invention contemplâtes various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molécules are nonsuperimposeable mirror images of one another. “Diastereomers” are stereoisomers that hâve at least two asymmetric atoms, but which are not mirror-images of each other.
[0045] The compounds disclosed herein and their pharmaceutically acceptable salts may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The présent invention is meant to include ail such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution ofthe racemate (or the racemate of a sait or dérivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of géométrie asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z géométrie isomers.
[0046] Compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. Ail such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed.
[0047] Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds hâve structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), nC, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36C1 and 125I. Varions isotopically labeled compounds of the présent disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, détection or imaging techniques, such as positron émission tomography (PET) or single-photon émission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and préparations described below by substituting a readily available isotopically labeled reagent for a nonisotopically labeled reagent
[0048] The disclosure also includes “deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molécule. Such compounds may exhibit increased résistance to metabolism and thus be useful for increasing the half-life of any compound of Formula I when administered to a mammal, e.g. a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens hâve been replaced by deuterium.
[0049] Deuterium labelled or substituted therapeutic compounds of the disclosure may hâve improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excrétion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F labeled compound may be useful for PET or SPECT studies.
[0050] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to hâve hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
[0051] Furthermore, the présent disclosure provides pharmaceutical compositions comprising at least one compound of the présent disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable sait or solvaté thereof as active ingrédient together with a pharmaceutically acceptable carrier.
[0052] “Pharmaceutical composition” means one or more active ingrédients, and one or more inert ingrédients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingrédients, or from dissociation of one or more of the ingrédients, or from other types of reactions or interactions of one or more of the ingrédients. Accordingly, the pharmaceutical compositions of the présent disclosure encompass any composition made by admixing at least one compound of the présent disclosure and a pharmaceutically acceptable carrier.
List of Abbreviations and Acronyms
Abbreviation | Meaning |
(±)-BINAP | (±)-2,2'-Bis(diphenylphosphino)-l ,1 '-binaphthalene |
2-MeTHF | 2-methyl tetrahydrofuran |
ACNorMeCN | Acetonitrile |
aq. | aqueous |
Bn | Benzyl |
BOC or Boc | AButyloxycarbonyl |
BSA | Bovine sérum albumin |
BSS | Balanced Sait Solution |
calcd | calculated |
DAST | (diethylamino)sulfur trifluoride |
DCM | Dichloromethane |
DIBAL-H | Diisobutylaluminum hydride |
DMF | Dimethylformamide |
DMSO | Dimethylsulfoxide |
EA | Ethyl acetate |
EDTA | Ethylenediaminetetraacetic acid |
ESI | Electronspray lonization |
Et | Ethyl |
EtzO | Diethyl ether |
EtOAc | Ethyl acetate |
FBS | Fêtai bovine sérum |
h or hr(s) | Hour(s) |
HATU | 1 -[Bis(dimethylamino)methylene]-1//-1,2,3triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate |
HPLC | High performance liquid chromatography |
IPA | Isopropyl alcohol |
IPTG | Isopropyl β-D-l -thiogalactopyranoside |
LCMS or | Liquid Chromatography Mass Spectrometiy |
LC/MS
Me | Methyl |
MEM | Minimum Essential Medium |
MeOH | Methanol |
min | Minute(s) |
MS | Mass Spectrometry |
m/z | Mass-to-charge ratio |
NADPH | Dihydronicotinamide-adenine dinucleotide phosphate |
NMP | N-methylpyrrolidone |
NMR | Nuclear Magnetic Résonance spectroscopy |
n-BuLi | n-butyllithium |
rpm | Révolutions per minute |
PE | Petroleum ether |
RT or rt | Room température |
sat. | saturated |
TB AF | Tetrabutylammonium fluoride |
TBDMS | /-butyldimethylsilyl |
TB S | i-butyldimethylsilyl |
TEMPO | 2,2,6,6-Tetramethylpiperidine 1-oxyl |
TFA | Trifluoroacetic acid |
THF | tetrahydrofuran |
TMS | trimethylsilyl |
UPLC | Ultra Performance Liquid Chromatography |
Compounds
[0053] Provided herein are compounds according to Formula (I):
(I) wherein:
Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, Ci-4-alkoxy, halo-Ci-4-alkoxy, -CH2F, -CHF2, and -CF3;
Y is N or CH;
A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently selected from halogen, Ci-4-alkoxy, halo-Ci-4-alkoxy, Ci-4-alkyl, and haloCi-4-alkyl;
Z is isoxazole substituted with R1 or pyrazole substituted with R1;
R1 is Ci-4-alkyl or Cs^-cycloalkyl, wherein said Ci-4-alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, Ci-3-alkoxy, and fluoro-Ci-3-alkoxy, and said C3-6-cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, Ci-3-alkyl, fluoro-Ci-3-alkyl, C1-3alkoxy, and fluoro-Ci-3-alkoxy;
R2 and R3 are independently selected from hydrogen, halogen, methoxy, -CF3, -CHF2, CH2F, -OCH2F, -OCHF2, -OCF3, and methyl;
R4 is -CO2R5 or -C(O)NR5R6;
R5 is hydrogen, Ci-6-alkyl, or halo-Ci^-alkyl; and
R6 is hydrogen or Ci-6-alkyl, wherein said Ci^-alkyl is optionally substituted with 1 to 6 substituents independently selected from halogen, -SO3H, and -CO2H;
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
[0054] One embodiment provides for compounds of Formula (la):
(la) wherein:
Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, Ci-i-alkoxy, halo-Ci-4-alkoxy, -CH2F, -CHF2, and -CF3;
Y is N or CH;
A is pyridylene or phenylene, each of which is optionally substituted with one or two groups independently selected from halogen, Ci-i-alkoxy, halo-Ci-i-alkoxy, Ci-4-alkyl, and haloC1-4-alkyl;
R1 is Ci-4-alkyl or Cs^-cycloalkyl, wherein said Ci-i-alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, Ci-3-alkoxy, and fluoro-Ci-3-alkoxy, and said C3-6-cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxyl, Ci-3-alkyl, fluoro-Ci-3-alkyl, Ci-3-alkoxy, and fluoro-Ci-3alkoxy;
R2 and R3 are independently selected from hydrogen, halogen, methoxy, -CF3, -CHF2, CH2F, -OCH2F, -OCHF2, -OCF3, and methyl;
R4 is -CO2R5 or -C(O)NR5R6;
R5 is hydrogen, Cj-6-alkyl, or halo-Ci^-alkyl;
R6 is hydrogen or Ci-6-alkyl, wherein said Ci^-alkyl is optionally substituted with 1 to 6 substituents independently selected from halogen, -SO3H, and -CO2H;
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
[0055] One embodiment provides for compounds of formula (la):
(la) wherein:
Q is phenylene optionally substituted with one or two halogen;
Y is N or CH;
A is pyridylene optionally substituted with one or two groups independently selected from halogen and Ci-4-alkoxy;
R1 is Ci-4-alkyl or Cs-c-cycloalkyl;
R2 and R3 are independently selected from hydrogen and halogen;
R4 is -CO2R5 or -C(O)NR5R6;
R5 is hydrogen; and
R6 is Ci-2-alkyl optionally substituted with -CO2H or -SO3H;
or pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
[0056] In one embodiment, Q is phenylene or pyridylene, each of which is optionally substituted with one or two substituents independently selected from halogen, methyl, -CHF2, and -CF3. In some embodiments, Q is phenylene optionally substituted with one or two substituents independently selected from halogen, methyl, and -CF3. In some embodiments, Q is pyridylene optionally substituted with one or two substituents independently selected from halogen, methyl, and -CF3.
[0057] In one embodiment, Q is phenylene optionally substituted with one or two halogen. In some embodiments, Q is pyridylene optionally substituted with one or two halogen. In some embodiments, Q is phenylene optionally substituted with one or two chloro. In some embodiments, Q is pyridylene optionally substituted with one or two chloro.
[0058] In one embodiment, Q is phenylene substituted with one chloro. In some embodiments, Q is pyridylene substituted with one chloro.
[0059] In one embodiment, R1 is Ci-4-alkyl. In some embodiments, R1 is C3-6-cycloalkyl. In some embodiments, R1 is cyclopropyl or methyl. In some embodiments, R1 is cyclopropyl.
[0060] In one embodiment, R2and R3 are not both hydrogen. In some embodiments, R2and R3 are independently selected from hydrogen, halogen, methoxy, -OCHF2, -OCF3, and methyl.
In some embodiments, R2 and R3 are independently selected from halogen, methoxy, -OCHF2, OCF3, and methyl.
[0061] In one embodiment, R2 and R3 are halogen. In some embodiments, R2 and R3 are chloro.
[0062] In one embodiment, one of R2 and R3 is a halogen and the other is hydrogen. In one embodiment, one of R2and R3 is a chloro and the other is hydrogen. In some embodiments, one of R2 and R3 is a fluoro and the other is hydrogen.
[0063] In one embodiment, Y is N. In some embodiments, Y is CH.
[0064] In one embodiment, A is pyridylene optionally substituted with one or two halogen. In some embodiments, A is pyridylene optionally substituted with one or two Ci-4-alkoxy.
[0065] In one embodiment, A is pyridylene substituted with one fluoro. In some embodiments, A is pyridylene substituted with one methoxy. In one embodiment, A is unsubstituted pyridylene.
[0066] In one embodiment, A is phenylene optionally substituted with one or two halogen. In one embodiment, A is phenylene optionally substituted with one or two Ci-4-alkoxy.
[0067] In one embodiment, A is phenylene substituted with one fluoro. In one embodiment, A is phenylene substituted with one methoxy. In one embodiment, A is unsubstituted phenylene.
[0068] In one embodiment, R4 is —CO2R5, and R5 is hydrogen. In one embodiment, R4 is — CO2R5 and R5 is Ci-6-alkyl or halo-Ci-6-alkyl.
[0069] In one embodiment, R4 is -C(O)NR5R6, R5 is Ci-e-alkyl or halo-Ci-6-alkyl, and R6 is Cu 2-alkyl, wherein said Ci-2-alkyl is substituted with -SO3H or -CO2H.
[0070] In one embodiment, R4 is -C(O)NR5R6, R5 is hydrogen, and R6 is Ci-2-alkyl, wherein said Ci-2-alkyl is substituted with -SO3H or -CO2H.
[0071] In one embodiment, R4-A is:
'—N , wherein the pyridylene is optionally substituted with one or two groups independently selected from halogen, Ci-4-alkoxy, halo-Ci-i-alkoxy, Ci-i-alkyl, and halo-Ci-4alkyl.
[0072] In one embodiment, R4-A is:
[0073] In one embodiment, R4-A is:
[0074] In one embodiment, R4-A is:
[0076] In one embodiment, provided is a compound selected from the group consisting of:
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
[0077] In one embodiment, provided herein is a compound having the following formula:
or a pharmaceutically acceptable sait thereof.
[0078] In one embodiment, provided herein is a compound having the following formula:
[0079] The Chemical name of each of these compounds is provided in Table 1 below.
Table 1
Example | Structure | IUP AC Name |
1 | X-o F | 2-(3-(2-chloro-4-((5cyclopropyl-3 -(2,4difluorophenyl)isoxazol-4yl)methoxy)phenyl)-3 hydroxyazetidin-1 yl)isonicotinic acid |
2 | O O ° ô °7\ Z O^^À^ O I | 2-(3-(2-chloro-4-((5cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4y l)methoxy)phenyl)-3 hydroxyazetidin-1 yl)isonicotinic acid |
3 | F <3 o /—( λοη ,—. N HO V )=7 Cl CI^Jï^CI F | 6-(3-(2-chloro-4-((5cyclopropyl-3 -(2,6-dichloro-4fluorophenyl)isoxazol-4y l)methoxy)phenyl)-3 hydroxyazetidin-1 -yl)-5fluoronicotinic acid |
4 | v y° / \ / N\/ \ N HO \=n )=7 Cl θΐΎΑγ-θ1 F | 6-(3-(2-chloro-4-((3-(2,6dichloro-4-fluorophenyl)-5methylisoxazol-4yl)methoxy)phenyl)-3 hydroxyazetidin-1 -yl)-5fluoronicotinic acid |
5 | J rVN^ / CI^X^CI HO2cA^N cl iQf F | 6-(3-(2-chloro-4-((4cyclopropyl-1 -(2,6-dichloro-4fluorophenyl)-! H-pyrazol-5 y l)methoxy)phenyl)-3 hydroxyazetidin-1 -y 1) - 5 fluoronicotinic acid |
6 | ZT° OH// ck/X .ci < J ci η η N OMe F | 5-((lS,3S)-3-(2-chloro-4-((5cyclopropyl-3 -(2,6-dichloro-4fluorophenyl)isoxazol-4y l)methoxy)phenyl)-3 hydroxycyclobutyl)-6methoxynicotinic acid |
7 | \-q ci^X/Ci JJ / CI ir tl LJ hn ηρ L F θ' OH | 2-(6-(3 -(2-chloro-4-((5cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4yl)methoxy)phenyl)-3 hydroxyazetidin-1 -y l)-5fluoronicotinamido)ethane-l sulfonic acid |
8 | Z o i o Ζ=λ Z v-o \ z ζ^λ ιγ Q (° Δ o | (6-(3-(2-chloro-4-((5cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4yl)methoxy)phenyl)-3 hydroxyazetidin-1 -yl)-5fluoronicotinoyl)glycine |
Pharmaceutical Compositions and Modes of Administration
[0080] The présent disclosure further provides pharmaceutical compositions comprising at least one compound of the présent disclosure, or a prodrug, a pharmaceutically acceptable sait, or solvaté thereof as active ingrédient together with a pharmaceutically acceptable carrier.
[0081] The pharmaceutical composition of the présent disclosure may additionally comprise one or more other compounds as active ingrédients like a prodrugor other nuclear receptor modulators.
[0082] The compositions are suitable for oral, rectal, topical, parentéral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will dépend on the nature and severity of the conditions being treated and on the nature of the active ingrédient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
[0083] In practical use, the compounds of the présent disclosure can be combined as the active ingrédient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of préparation desired for administration, e.g., oral or parentéral (including intravenous). In preparing the compositions for oral dosage form, any ofthe usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid préparations, such as, for example, suspensions, élixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid préparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral préparations being preferred over the liquid préparations.
[0084] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and préparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
[0085] The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnésium stéarate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
[0086] Various other materials may be présent as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or élixir may contain, in addition to the active ingrédient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
[0087] Since the compounds of the présent disclosure mostly represent carboxylic acids or similar anionic isosters thereof, and since sait forms of ionic compounds can substantially affect bioavailability, the compounds of the présent disclosure may also be used as salts with various countercations to yield an orally available formulation. Such pharmaceutically acceptable cations may be amongst others mono- or bivalent ions such as ammonium, the alkaline metals sodium or potassium or the alkaline earth metals magnésium or calcium, certain pharmaceutically acceptable amines such as tris(hydroxymethyl)aminomethane, ethylendiamine, diethylamine, piperazine or others, or certain cationic amino acids such as lysine or arginine.
[0088] The compounds of the présent disclosure may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these préparations contain a preservative to prevent the growth of microorganisms.
[0089] The pharmaceutical forms suitable for injectable use include stérile aqueous solutions or dispersions and stérile powders for the extemporaneous préparation of stérile injectable solutions or dispersions. In ail cases, the form must be stérile and must be fluid to the extent that easy syringability existe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, éthanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
[0090] Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the présent disclosure. For example, oral, rectal, topical, parentéral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aérosols, and the like. In some embodiments, compounds of the présent disclosure are administered orally.
Kits
[0091] Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.
[0092] Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
Treatment Methods and Uses
[0093] “Treatment” or “treating” is an approach for obtaining bénéficiai or desired résulte including clinical résulte. Bénéficiai or desired clinical résulte may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the régression of clinical symptoms (e.g., ameliorating the disease State, providing partial or total remission of the disease or condition, enhancing effect of another médication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
[0094] “Prévention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a fàmily history of the disease or condition.
[0095] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.
[0096] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of Cot activity. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and âge ofthe subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
[0097] The disclosure further relates to the use of said compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds. Further the présent disclosure relates to the use of said compounds for the préparation of a médicament for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.
[0098] Also provided herein are methods of treating a patient having a FXR mediated condition comprising administering a compound of formula (I), or pharmaceutically acceptable sait thereof, or a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable sait thereof.
[0099] In some embodiments, a compound of formula (I), or pharmaceutically acceptable sait thereof, or a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable sait thereof is provided for use in the treatment of a FXR mediated condition.
[0100] In some embodiments, a compound of formula (I), or pharmaceutically acceptable sait thereof, or a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable sait thereof, is provided for the manufacture of a médicament for the treatment of a FXR mediated condition.
[0101] In some embodiments, the FXR mediated condition is:
a chronic intrahepatic or some form of extrahepatic cholestatic condition;
liver fibrosis;
an obstructive inflammatory disorder of the liver, chronic inflammatory disorder of the liver;
liver cirrhosis;
liver steatosis or an associated syndrome;
cholestatic or fibrotic effects that are associated with alcohol-induced cirrhosis or with viral-bome forms of hepatitis;
liver failure or liver ischemia after major liver resection;
chemotherapy associated steatohepatitis (CASH);
acute liver failure; or
Inflammatory Bowel Disease.
[0102] In some embodiments, the FXR mediated condition is:
a lipid and lipoprotein disorder;
Type I Diabètes;
Type II Diabètes;
clinical complications of Type I and Type II Diabètes selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of clinically manifest long term Diabètes;
Non-Alcoholic Fatty Liver Disease (NAFLD);
Non-Alcoholic Steatohepatitis (NASH);
obesity;
a metabolic syndrome selected from the group consisting of combined conditions of dyslipidemia, diabètes and abnormally high body-mass index;
acute myocardial infàrction;
acute stroke; or thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis.
[0103] In some embodiments, the FXR mediated condition is: a non-malignant hyperproliferative disorder; and a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis;
colon adenocarcinoma;
breast cancer, pancréas adenocarcinoma;
Barrett's esophagus; or other forms of neoplastic diseases of the gastrointestinal tract and the liver.
[0104] In some embodiments, the FXR mediated condition is Non-Alcoholic Steatohepatitis (NASH).
[0105] In some embodiments, the présent disclosure relates to the use of compounds according to Formula (I) in the préparation of a médicament for the prophylaxis and/or treatment of chronic intrahepatic or some forms of extrahepatic cholestatic conditions, of liver fibrosis, of acute intraheptic cholestatic conditions, of obstructive or chronic inflammatory disorders that arise out of improper bile composition, of gastrointestinal conditions with a reduced uptake of dietary fat and fat-soluble dietary vitamins, of inflammatory bowel diseases, of lipid and lipoprotein disorders, of Type Π Diabètes and clinical complications of Type I and Type Π Diabètes, of conditions and diseases which resuit from chronic fatty and fibrotic degeneration of organs due to enforced lipid and specifically triglycéride accumulation and subséquent activation of profibrotic pathways, of obesity and metabolic syndrome (combined conditions of dyslipidemia, diabètes and abnormally high body-mass index), of acute myocardial infarction, of acute stroke, of thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis, of persistant infections by intracellular bacteria or parasitic protozoae, of non-malignant hyperproliferative disorders, of malignant hyperproliferative disorders, of colon adenocarcinoma and hepatocellular carcinoma in particular, of liver steatosis and associated syndromes, of liver failure or liver malfunction as an outcome of chronic liver diseases or of surgical liver resection, of Hepatitis B infection, of Hepatitis C infection and/or of cholestatic and fibrotic effects that are associated with alcohol-induced cirrhosis or with viral-bome forms of hepatitis.
[0106] Médicaments as referred to herein may be prepared by conventional processes, including the combination of a compound according to the présent disclosure and a pharmaceutically acceptable carrier.
[0107] FXR is proposed to be a nuclear bile acid sensor. As a resuit, it modulâtes both, the synthetic output of bile acids in the liver and their recycling in the intestine (by regulating bile acid binding proteins). But beyond bile acid physiology, FXR seems to be involved in the régulation of many diverse physiological processes which are relevant in the etiology and for the treatment of diseases as diverse as cholestérol gallstones, metabolic disorders such as Type Π Diabètes, dyslipidemias or obesity, chronic inflammatory diseases such as Inflammatory Bowel Diseases or chronic intrahepatic forms of cholestasis and many other diseases.
[0108] FXR régulâtes a complex pattern of response genes in the liver and in the gastrointestinal tract. The gene products hâve impact on diverse physiological processes. In the course of functional analysis of FXR, the first regulatory network that was analyzed was the régulation of bile acid synthesis. While the LXRs induce the key enzyme of the conversion of cholestérol into bile acids, Cyp7Al, via the induction of the regulatory nuclear receptorLRH-1,
FXR represses the induction of Cyp7Al via the upregulation of mRNA encoding SHP, a further nuclear receptor that is dominant répressive overLRH-1. Since FXR binds the end products of this pathway, primary bile acids such as cholic acid (CA) or CDCA, this can be regarded as an example of feedback inhibition on the gene expression level. Parallel to the repression of bile acid synthesis via SHP, FXR induces a range of so-called ABC (for ATP-binding cassette) transportera that are responsible for the export of toxic bile acids from the hépatocyte cytosol into the canaliculi, the small bile duct ramifications where the bile originates. This hepatoprotective fonction of FXR became first apparent with the analysis of FXR knockout mice. where under- or overexpression of several ABC-transporters in the liver was shown. Further detailed analysis revealed that the major bile sait excretory pump BSEP or ABCB11 (as well as the key enzyme which médiates lipid transfer from lipoproteins to phospholipids, PLTP, and the two key canalicular membrane transportera for phospholipids, MRP-2 (ABCC4) and MDR-3 (ABCB4),are direct targets for ligand-directed transcriptional activation by FXR.
[0109] The fect that FXR seems to be the major métabolite sensor and regulator for the synthesis, export and re-circulation of bile acids suggested the use of FXR ligands to induce bile flow and change bile acid composition towards more hydrophilic composition. With the development of the first synthetic FXR ligand GW4064 as a tool compound and of the semisynthetic artifîcial bile acid ligand 6-alpha-ethyl-CDCA, the effects of superatimulation of FXR by potent agonists could be analyzed. It was shown that both ligands induce bile flow in bile duct ligated animais. Moreover, in addition to choleretic effects, also hepatoprotective effects could be demonstrated. This hepatoprotective effect was forther narrowed down to an anti-fibrotic effect that results from the repression of Tissue Inhibitora of Matrix-Metalloproteinases, ΊΊΜΡ-1 and 2, the induction of collagen-deposit resolving Matrix-Metalloproteinase 2 in hepatic stellate cells and the subséquent réduction of alpha-collagen mRNA and Transforming growth factor beta (TGF-beta) mRNA which are both pro-fibrotic factors by FXR agonists. Furthermore, anticholestatic activity was demonstrated in bile-duct ligated animal models as well as in animal models of estrogen-induced cholestasis.
[0110] Genetic studies demonstrate that in hereditary forms of cholestasis (Progressive Familiar Intrahepatic Cholestasis = PFIC, Type I — IV) either nuclear localization of FXR itself is reduced as a conséquence of a mutation in the FIC1 gene (in PFIC Type I, also called Byler's
Disease) (F. Chen et al., Gastroenterology 2004,126, 756; L. Alvarez et al., Hum. Mol. Genet. 2004,13, 2451 ) or levels of the FXR target gene encoding MDR-3 phospholipid export pump are reduced (in PFIC Type ΠΙ). Taken together there is a growing body of evidence that FXR binding compounds will demonstrate substantial clinical utility in the therapeutic regimen of chronic cholestatic conditions such as Primary B iliary Cirrhosis (PBC) or Primary Sclerosing Cholangitis (PSC).
[0111] The deep impact that FXR activation has on bile acid metabolism and excrétion is not only relevant for cholestatic syndromes but even more directly for a therapy against gallstone formation. Cholestérol gallstones form due to low solubility of cholestérol that is actively pumped out of the liver cell into the lumen of the canaliculi. It is the relative percentage of content of the three major components, bile acids, phospholipids and free cholestérol that détermines the formation of mixed micelles and hence apparent solubility of free cholestérol in the bile. FXR polymorphisms map as quantitative trait loci as one factor contributing to gallstone disease. Using the synthetic FXR tool compound GW4064 it could be demonstrated that activation of FXR leads to an improvement of the Cholestérol Saturation Index (CSI) and directly to an abolishment of gallstone formation in C57L gallstone susceptible mice whereas drug treatment in FXR knockout mice shows no effect on gallstone formation.
[0112] These results qualify FXR as a good target for the development of small molécule agonists that can be used to prevent cholestérol gallstone formation or to prevent re-formation of gallstones after surgical removal or shockwave lithotripsy.
[0113] Thus, in one embodiment of the disclosure, the compound according to Formula (I) and pharmaceutical compositions comprising said compound is used for the prophylaxis and/or treatment of obstructive or chronic inflammatory disorders that arise out of improper bile composition such as cholelithiasis also known as cholestérol gallstones.
[0114] Beyond its strong hepatoprotective and choleretic as well as anti-fibrotic effects that FXR shows upon small molécule stimulated activation in the liver, FXR seems to hâve a rôle in protecting the intestine from neoplastic transformation and from the development of polyps and their transition into adenocarcinoma in the gut Similar to the situation in the intestine absence of FXR leads to a high increase in the formation of Hepatocellular Cacrcinoma (HCC), the most prominent form of liver cancer. Whereas a functional FXR prevents the formation of colon adenocarcinoma and hepatocellular carcinoma, FXR activation induces liver régénération after hepatectomy.
[0115] The combined hepatoprotective, anti-neoplastic and liver regenerative effects associated with FXR activation can be therapeutically exploited for the use of FXR agonists in the treatment of severe liver diseases. In one embodiment, the compounds according to the disclosure and pharmaceutical compositions comprising said compounds are used in the treatment of liver diseases such as HCC, stimulation of liver regrowth and amelioration of side effects associated with major liver resection, liver cirrhosis independent of the etiology and prévention or treatment of liver ischemia in the course of liver transplantation or major liver surgery.
[0116] Since the discovery of the first synthetic FXR agonist and its administration to rodents it became évident that FXR is a key regulator of sérum triglycérides. Over the past six years accumulating evidence has been published that activation of FXR by synthetic agonists leads to significant réduction of sérum triglycérides, mainly in the form of reduced VLDL, but also to reduced total sérum cholestérol.
[0117] But the lowering of sérum triglycérides is not a stand alone effect. Treatment of db/db or ob/ob mice with synthetic FXR agonist GW4064 resulted in marked and combined réduction of sérum triglycérides, total cholestérol, free fàtty acids, ketone bodies such as 3-OH Butyrate. Moreover, FXR activation engages with the intracellular insulin signaling pathway in hépatocytes, resulting in reduced output of glucose from liver gluconeogenesis but concomitant increase in liver glycogen. Insulin sensitivity as well as glucose tolérance were positively impacted by FXR treatment. An effect on réduction of body weight was also recently observed in mice overfed with a high lipid diet. This weight loss effect might results from FXR's induction of FGF-19, a fibroblast growth factor that is known to lead to weight loss and athletic phenotype. The effect of FXR agonist on réduction of body weight has been demonstrated.
[0118] Taken together, these pharmacological effects of FXR agonists can be exploited in different therapeutic ways: FXR binding compounds are thought to be good candidates for the treatment of Type Π Diabètes because of their insulin sensitization, glycogenogenic, and lipid lowering effects.
[0119] In one embodiment, the compounds according to the disclosure and pharmaceutical compositions comprising said compounds are used in the prophylaxis and/or treatment of Type Π Diabètes which can be overcome by FXR-mediated upregulation of systemic insulin sensitivity and intracellular insulin signalling in liver, increased peripheral glucose uptake and metabolisation, increased glycogen storage in liver, decreased output of glucose into sérum from liver-bome gluconeogenesis.
[0120] In a further embodiment, said compounds and pharmaceutical compositions are used for the prophylaxis and/or treatment of chronic intrahepatic, such as PBC, PSC, progressive familiar cholestasis (PFIC), alcohol-induced cirrhosis and associated cholestasis, and some forms of extrahepatic cholestatic conditions, or liver fibrosis.
[0121] The disclosure also relates to a compound of Formula (I) or a pharmaceutical composition comprising said compound for the prophylaxis and/or treatment of gastrointestinal conditions with a reduced uptake of dietary fat and fat-soluble dietary vitamins which can be overcome by increased intestinal levels of bile acids and phospholipids.
[0122] In a further embodiment, said compound or pharmaceutical composition is used for preventing and/or treating a disease selected from the group consisting of lipid and lipoprotein disorders such as hypercholesterolemia, hypertriglyceridemia, and atherosclerosis as a clinically manifest condition which can be ameliorated by FXR's bénéficiai effect on lowering total plasma cholestérol, lowering sérum triglycérides, increasing conversion of liver cholestérol into bile acids and increased clearance and metabolic conversion of VLDL and other lipoproteins in the liver.
[0123] In one further embodiment, said compound and pharmaceutical composition are used for the prophylaxis and/or treatment of diseases where the combined lipid lowering, anticholestatic and anti-fîbrotic effects of FXR-targeted médicaments can be exploited for the treatment of liver steatosis and associated syndromes such as Non-Alcoholic Steatohepatitis (NASH), or for the treatment of cholestatic and fîbrotic effects that are associated with alcoholinduced cirrhosis, or with viral-bome forms of hepatitis.
[0124] In conjunction with the hypolipidémie effects it was also shown that loss of fùnctional FXR leads to increased atherosclerosis in ApoE knockout mice. Therefore, FXR agonists might hâve clinical utility as anti-atherosclerotic and cardioprotective drugs. The downregulation of Endothelin-1 in Vascular Smooth Muscle Cells might also contribute to such bénéficiai therapeutic effects.
[0125] The disclosure also relates to a compound according to Formula (I) or a pharmaceutical composition comprising said compound for préventive and posttraumatic treatment of a cardiovascular disorder, such as acute myocardial infarction, acute stroke, or thrombosis which occur as an endpoint of chronic obstructive atherosclerosis.
[0126] Beyond controlling intestinal and colonie polyp formation, FXR seems to be expressed in breast cancer tissue and cell lines but not in healthy breast tissue and seems to interact with the Estrogen Receptor in ER positive breast cancer cells.
[0127] This would allow to regard FXR also as a potential target for the treatment of proliférative diseases, especially metastasizing cancer forms that express a small molécule responsive form of FXR.
[0128] In a further embodiment, said compounds and pharmaceutical compositions are used for the prophylaxis and/or treatment of malignant hyperproliferative disorders such as different forms of cancer, specifically certain forms of breast, liver or colon cancer where interférence with an FXR ligand will hâve a bénéficiai impact.
[0129] Finally, FXR seems also to be involved in the control of antibacterial defense in the intestine although an exact mechanism is not provided. From these published data, however, one can conclude that treatment with FXR agonists might hâve a bénéficiai impact in the therapy of Inflammatory Bowel Disorders (IBD), in particular those forms where the upper (ileal) part of the intestine is affected (e.g. ileal Crohn's disease) because this seems to be the site of action of FXR's control on bacterial growth. In IBD, the desensitization of the adaptive immune response is somehow impaired in the intestinal immune System. Bacterial overgrowth might then be the causative trigger towards establishment of a chronic inflammatory response. Hence, dampening of bacterial growth by FXR-bome mechanisms might be a key mechanism to prevent acute inflammatory épisodes.
[0130] Thus, the disclosure also relates to a compound according to Formula (I) or a pharmaceutical composition comprising said compound for preventing and/or treating a disease related to an Inflammatory Bowel Disease, such as Crohn's disease or Colitis ulcerosa. FXRmediated restoration of intestinal barrier function and réduction in non-commensal bacterial load is believed to be helpful in reducing the exposure of bacterial antigens to the intestinal immune System and can therefore reduce inflammatory responses.
[0131] The disclosure further relates to a compound or pharmaceutical composition for the prophylaxis and/or treatment of obesity and associated disorders such as metabolic syndrome (combined conditions of dyslipidemias, diabètes and abnormally high body-mass index) which can be overcome by FXR-mediated lowering of sérum triglycérides, blood glucose and increased insulin sensitivity and FXR-mediated weight loss.
[0132] In a further embodiment, the compounds or pharmaceutical composition of the présent disclosure are useful in preventing and/or treating clinical complications of Type I and Type Π Diabètes. Examples of such complications include Diabetic Nephropathy, Diabetic Retinopathy, Diabetic Neuropathies, or Peripheral Arterial Occlusive Disease (PAOD). Other clinical complications of Diabètes are also encompassed by the présent disclosure.
[0133] Furthermore, conditions and diseases which resuit from chronic fatty and fibrotic degeneration of organs due to enforced lipid and specifically triglycéride accumulation and subséquent activation of profibrotic pathways may also be prevented and/or treated by administering the compounds or pharmaceutical composition of the présent disclosure. Such conditions and diseases encompass NASH and chronic cholestatic conditions in the liver, Glomerulosclerosis and Diabetic Nephropathy in the kidney, Macula Degeneration and Diabetic Retinopathy in the eye and neurodegenerative diseases, such as Alzheimer's Disease in the brain, or Diabetic Neuropathies in the peripheral nervous System.
Dosage
[0134] The effective dosage of active ingrédient employed may vaiy depending on the particular compound employed, the mode of administration, the condition being treated and the severity ofthe condition being treated. Such dosage may be ascertained readily by a person skilled in the art
[0135] When treating or preventing FXR mediated conditions for which compounds of the présent disclosure are indicated, generally satisfactory results are obtained when the compounds ofthe présent disclosure are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight In some embodiments, the compounds of the présent disclosure are given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1 milligram to about 1000 milligrams, or from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dosage is from about 1 milligram to about 900 milligrams, about 10 milligrams to about 800 milligrams, about 20 milligrams to about 700 milligrams, about 30 milligrams to about 600 milligrams, about 40 milligrams to about 550 milligrams, or about 50 milligrams to about 400 milligrams.
[0136] The compounds of the présent application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment Treatment cycles are well known in cancer chemotherapy, and are frequently altemated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.
[0137] In a particular embodiment, the methods provided herein comprise administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by incréments until clinical efficacy is achieved. Incréments of about 5,10,25, 50, or
100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
Combination Thérapies
[0138] In some embodiments, a compound disclosed herein is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are a(n) ACE inhibitor, Acetyl CoA carboxylase inhibitor, Adenosine A3 receptor agonist, Adiponectin receptor agonist, AKT protein kinase inhibitor, AMP-activated protein kinases (AMPK), Amylin receptor agonist, Angiotensin H AT-1 receptor antagonist, Autotaxin inhibitors, Bioactive lipid, Calcitonin agonist, Caspase inhibitor, Caspase-3 stimulator, Cathepsin inhibitor, Caveolin 1 inhibitor, CCR2 chemokine antagonist, CCR3 chemokine antagonist, CCR5 chemokine antagonist, Chloride channel stimulator, CNR1 inhibitor, Cyclin DI inhibitor, Cytochrome P450 7A1 inhibitor, DGAT1/2 inhibitor, Dipeptidyl peptidase IV inhibitor, Endosialin modulator, Eotaxin ligand inhibitor, Extracellular matrix protein modulator, Famesoid X receptor agonist, Fatty acid synthase inhibitors, FGF1 receptor agonist, Fibroblast growth factor (FGF-15, FGF19, FGF-21) ligands, Galectin-3 inhibitor, Glucagon receptor agonist, Glucagon-like peptide 1 agonist, G-protein coupled bile acid receptor 1 agonist, Hedgehog (Hh) modulator, Hepatitis C virus NS3 protease inhibitor, Hépatocyte nuclear factor 4 alpha modulator (HNF4A), Hépatocyte growth factor modulator, HMG CoA reductase inhibitor, IL-10 agonist, IL-17 antagonist, Ileal sodium bile acid cotransporter inhibitor, Insulin sensitizer, integrin modulator, intereukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, Jak2 tyrosine kinase inhibitor, Klotho beta stimulator, 5-Lipoxygenase inhibitor, Lipoprotein lipase inhibitor, Liver X receptor, LPL gene stimulator, Lysophosphatidate-1 receptor antagonist, Lysyl oxidase homolog 2 inhibitor, Matrix metalloproteinases (MMPs) inhibitor, MEKK-5 protein kinase inhibitor, Membrane copper amine oxidase (VAP-1) inhibitor, Méthionine aminopeptidase-2 inhibitor, Methyl CpG binding protein 2 modulator, MicroRNA-21(miR-21) inhibitor, Mitochondrial uncoupler, Myelin basic protein stimulator, NACHT LRR PYD domain protein 3 (NLRP3) inhibitor, NAD-dependent deacetylase sirtuin stimulator, NADPH oxidase inhibitor (NOX), Nicotinic acid receptor 1 agonist, P2Y13 purinoceptor stimulator, PDE 3 inhibitor, PDE 4 inhibitor, PDE 5 inhibitor, PDGF receptor beta modulator, Phospholipase C inhibitor, PPAR alpha agonist, PPAR delta agonist, PP AR gamma agonist, PP AR gamma modulator, Protease-activated receptor-2 antagonist, Protein kinase modulator, Rho associated protein kinase inhibitor, Sodium glucose transporter-2 inhibitor, SREBP transcription factor inhibitor, STAT-1 inhibitor, Stearoyl CoA desaturase-1 inhibitor, Suppressor of cytokine signalling-1 stimulator, Suppressor of cytokine • signalling-3 stimulator, Transforming growth factor β (TGF-β), Transforming growth factor β activated Kinase 1 (TAK1), Thyroid hormone receptor beta agonist, TLR-4 antagonist, Transglutaminase inhibitor, Tyrosine kinase receptor modulator, GPCR modulator, nuclear hormone receptor modulator, WNT modulators, or YAP/TAZ modulator.
[0139] Non-limiting examples of the one or more additional therapeutic agents include:
ACE inhibitors, such as enalapril;
Acetyl CoA carboxylase (ACC) inhibitors, such as DRM-01, gemcabene, PF-05175157, and QLT-091382;
Adenosine receptor agonists, such as CF-102, CF-101, CF-502, and CGS21680;
Adiponectin receptor agonists, such as ADP-355;
Amylin/calcitonin receptor agonists, such as KBP-042;
AMP activated protein kinase stimulators, such as 0-304;
Angiotensin Π AT-1 receptor antagonists, such as irbesartan;
Autotaxin inhibitors, such as PAT-505, PAT-048, GLPG-1690, X-165, PF-8380, and AM-063;
Bioactive lipids, such as DS-102;
Cannabinoid receptor type 1 (CNR1) inhibitors, such as namacizumab and GWP-42004; Caspase inhibitors, such as emricasan;
Pan cathepsin B inhibitors, such as VBY-376;
Pan cathepsin inhibitors, such as VBY-825;
CCR2/CCR5 chemokine antagonists, such as cenicriviroc;
CCR2 chemokine antagonists, such as propagermanium;
CCR3 chemokine antagonists, such as bertilimumab;
Chloride channel stimulators, such as cobiprostone;
Diglyceride acyltransferase 2 (DGAT2) inhibitors, such as IONIS-DGAT2Rx; Dipeptidyl peptidase IV inhibitors, such as linagliptin;
Eotaxin ligand inhibitors, such as bertilimumab;
Extracellular matrix protein modulators, such as CNX-024;
Famesoid X receptor (FXR) agonists, such as AGN-242266, AKN-083, EDP-305, GNF5120, LJN-452, LMB-763, obeticholic acid, Px-102, Px-103, M790, M780, M450, M480, PX20606, EYP-001, and INT-2228;
Famesoid X receptor (FXR)/ G-protein coupled bile acid receptor 1(TGR5) agonists, such as INT-767;
Fatty acid synthase inhibitors, such as TVB-2640;
Fibroblast growth factor 19 (rhFGF19)/cytochrome P450 (CYP)7A1 inhibitors, such as NGM-282;
Fibroblast growth factor 21 (FGF-21) ligand, such as BMS-986171, BMS-986036;
Fibroblast growth factor 21(FGF-21)/glucagon like peptide 1 (GLP-1) agonists, such as YH-25723;
Galectin-3 inhibitors, such as GR-MD-02;
Glucagon-like peptide 1(GLP1R) agonists, such as AC-3174, liraglutide, semaglutide;
G-protein coupled bile acid receptor 1(TGR5) agonists, such as RDX-009, INT-777;
Heat shock protein 47 (HSP47) inhibitors, such as ND-L02-s0201;
HMG CoA reductase inhibitors, such as atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin;
IL-10 agonists, such as peg-ilodecakin;
Ileal sodium bile acid cotransporter inhibitors, such as A-4250, volixibat potassium ethanolate hydrate (SHP-262), and GSK2330672;
Insulin sensitizers, such as, KBP-042, MSDC-0602K, Px-102, RG-125 (AZD4076), and WP-100X;
beta Klotho (KLB)- FGF1 c agonist, such as NGM-313;
5-Lipoxygenase inhibitors, such as tipelukast (MN-001);
Lipoprotein lipase inhibitors, such as CAT-2003;
LPL gene stimulators, such as alipogene tiparvovec;
Liver X receptor (LXR) modulators, such as PX-L603, PX-L493, BMS-852927, T0901317, GW-3965, and SR-9238;
Lysophosphatidate-1 receptor antagoniste, such as BMT-053011, UD-009. AR-479, ITMN-10534, BMS-986020, and KI-16198;
Lysyl oxidase homolog 2 inhibitors, such as simtuzumab;
Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1 (SSAO/VAP-1) Inhibitors, such as PXS-4728A;
Méthionine aminopeptidase-2 inhibitors, such as ZGN-839;
Methyl CpG binding protein 2 modulators, such as mercaptamine;
Mitochondrial uncouplers, such as 2,4-dinitrophenol;
Myelin basic protein stimulators, such as olesoxime;
NADPH oxidase 1/4 inhibitors, such as GKT-831,
Nicotinic acid receptor 1 agonists, such as ARI-3037MO;
NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, such as KDDF-201406-03, and NBC-6;
Nuclear receptor modulators, such as DUR-928;
P2Y13 purinoceptor stimulators, such as CER-209;
PDE 3/4 inhibitors, such as tipelukast (MN-001);
PDE 5 inhibitors, such as sildenafil;
PDGF receptor beta modulators, such as BOT-191, BOT-509;
PPAR agonists, such as elafibranor (GFT-505), MBX-8025, deuterated pioglitazone Renantiomer, pioglitazone, DRX-065, saroglitazar, and IVA-337;
Protease-activated receptor-2 antagonists, such as PZ-235;
Protein kinase modulators, such as CNX-014;
Rho associated protein kinase (ROCK) inhibitors, such as KD-025;
Sodium glucose transporter-2(SGLT2) inhibitors, such as ipragliflozin, remogliflozin etabonate, ertugliflozin, dapagliflozin, and sotagliflozin;
SREBP transcription factor inhibitors, such as CAT-2003 and MDV-4463;
Stearoyl CoA desaturase-1 inhibitors, such as aramchol;
Thyroid hormone receptor beta agonists, such as MGL-3196, MGL-3745, VK-2809;
TLR-4 antagonists, such as JKB-121;
Tyrosine kinase receptor modulators, such as CNX-025;
GPCR modulators, such as CNX-023; and
Nuclear hormone receptor modulators, such as Px-102.
[0140] In certain spécifie embodiments, the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalibylic acid, AK-20, alipogene tiparvovec, aramehol, ARI-3037MO, ASP-8232, bertilimumab, Betaine anhydrous, BI-1467335, BMS-986036, BMS986171, BMT-053011, BOT-191, BTT-1023, CAT-2003, cenicriviroc, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dapagliflozin, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F351, GKT-831, GNF-5120, GR-MD-02, hydrochlorothiazide, icosapent ethyl ester, IMM-124-E, INT-767, IONIS-DGAT2Rx, ipragliflozin, Jrbesarta, propagermanium, IVA-337, JKB-121, KBGE-001, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LC-280126, linagliptin, liraglutide, LJN-452, LMB-763, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL3745, MSDC-0602K, namacizumab, NC-101, ND-L02-s0201, NGM-282, NGM-313, NGM386, NGM-395, norursodeoxycholic acid, 0-304, obeticholic acid, 25HC3S, olesoxime, PAT505, PAT-048, peg-ilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, RDX-009, remogliflozin etabonate, RG-125 (AZD4076), saroglitazar, semaglutide, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvaistatin, simvastatin), TCM-606F, TEV-45478, tipelukast (MN-001), TLY-012, TRX-318, jTVB-2640, UD-009, ursodeoxycholic acid, VBY376, VBY-825, VK-2809, vismodegib, volixibat potassium ethanolate hydrate (SHP-626), WP100X, WAV-301, WNT-974, and ZGN-839.
E^AMPLES
[0141] The following examples are included to demonstrate spécifie embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute spécifie modes for its practice. However, those of skill m the art should, in light of the présent disclosure, appreciate that many changes can be made in the spécifie embodiments which are disclosed and still obtain a like or similar resuit without departing from the spirit and scope of the disclosure.
[0142] The compounds of the présent disclosure can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplifîed by the following spécifie examples. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the présent disclosure claimed herein can be readily prepared. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure. The examples further illustrate details for the préparation of the compounds of the présent disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following préparative procedures can be used to préparé these compounds. For synthesizing compounds which are embodiments described in the présent disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. The instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described above. In general, compounds described herein are typically stable and isolatable at room température and pressure
[0143] The amine-free bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogen carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of the liberated aminefree base into an organic solvent, followed by évaporation. The amine-free base, isolated in this manner, can be further converted into another pharmaceutically acceptable sait by dissolution in an organic solvent, followed by addition of the appropriate acid and subséquent évaporation, précipitation or ciystallization. The carboxylic free acids corresponding to the isolated salts can be generated by neutralization with a suitable acid, such as aqueous hydrochloric acid, sodium hydrogen sulfate, sodium dihydrogen phosphate, and extraction ofthe liberated carboxylic-free acid into an organic solvent, followed by évaporation. The carboxylic acid, isolated in this manner, can be further converted into another pharmaceutically acceptable sait by dissolution in an organic solvent, followed by addition of the appropriate base and subséquent évaporation, précipitation or crystallization.
[0144] An illustration of the préparation of compounds of the présent disclosure is shown below. Unless otherwise indicated in the schemes, the variables hâve the same meaning as described above. The examples presented below are intended to illustrate particular embodiments of the disclosure. Suitable starting materials, building blocks and reagents employed in the synthesis as described below are commercially available from Sigma-Aldrich or Acros Organics, for example, or can be routinely prepared by procedures described in the literature, for example in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition; John Wiley & Sons or T. Eicher, S. Hauptmann The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application, 2nd édition, Wiley-VCH 2003; Fieser et al. “Fiesers' Reagents for organic Synthesis” John Wiley & Sons 2000.
General Synthetic Scheme
[0145] Compounds of Formula (I) wherein Y is N can be synthesized according to the following general synthetic scheme.
[0146] In the general synthetic scheme above, X is a leaving group, PG is a protecting group, and the remaining variables are as provided herein. A compound of formula (C) can be prepared by reacting a compound of formula (A) with a compound of formula (B) in the presence of a base to form a compound of formula (C). A compound of formula (D) is formed from a compound of formula (C) under appropriate deprotection conditions. A compound of formula (D) can be combined with a compound of formula (E) in the presence of a base to give a compound of Formula (I).
[0147] Appropriate compounds of structure (A) and (B) can be prepared according to the spécifie methods described in the following Examples or by methods known in the art. In some embodiments, X is halo. In some embodiments, PG is BOC.
General Synthesis 1
Step 1
Step 4
Stepl: 2-(3-hydroxyazetidin-l-yl)isonicotinonitriIe (la)
[0148] Potassium carbonate (4.6 g, 33 mmol) was added to 2-chloro-4-pyridinecarbonitrile (2.0 g, 14.4 mmol) and 3-hydroxyazetidine hydrochloride (1.7 g, 16 mmol) in NMP (12 mL) at room température, and the mixture was heated to 80 °C for 2 hrs in a sealed tube. The mixture was cooled to room température, treated with H2O and extracted with EtOAc. The organic layers, were washed with brine, dried with NazSO4 and concentrated. Purification by chromatography (ISCO 24 g silica column) using a gradient 1:1 hexanes/ EtOAc - 100% EtOAc gave 2-(3hydroxyazetidin-1 -yl)isonicotinonitrile (la).
Step 2: 2-(3-oxoazetidin-l-yl)isonicotinonitriIe (1b)
[0149] N-methylmorpholine (1.9 g, 16 mmol) then tetrapropylammonium perruthenate (190 mg, 0.5 mmol) were added to 2-(3-hydroxyazetidin-l-yl)isonicotinonitrile (1.9 g, 10.7 mmol) in CH2CI2 (200 mL) with molecular sieves (1 g, activated powdered, 4 Â) at room température. After 20 minutes with vigorous stirring, the mixture was fiitered through a pad of Celite and concentrated. Purification by chromatography (ISCO 24 g silica column) using a gradient 100% hexanes -1:3 hexanes/EtOAc gave 2-(3-oxoazetidin-l-yl)isonicotinonitrile (1b).
Synthesis of le: (4-bromo-3-chIorophenoxy)(tert-butyl)dimethylsiIane (le)
[0150] To the solution of 4-bromo-3-chlorophenol (250 g, 1.21 mol) and TBSC1 (272 g, 1.81 mol) in DMF (2.0 L) was added imidazole (164 g, 2.41 mol). Then the reaction was stirred at 30 °C for 12 h. The reaction mixture was poured into H2O (3 L) and extracted with EtOAc (2 L) twice. The combined organic layers were washed with H2O (IL) and brine (1 L), dried over Na2SO4, fiitered and concentrated in vacuo. Purification by silica gel chromatography eluted with petroleum ether gave (4-bromo-3-chlorophenoxy)(tert-butyl)dimethylsilane (le).
Step 3: 2-(3-(4-((tert-ButyIdimethylsilyl)oxy)-2-chIorophenyl)-3-hydroxyazetidin-lyl)isonicotinonitrile (Id)
[0151] Isopropylmagnesium chloride lithium chloride complex (1.3 ml, 1.7 mmol, 1.5 M in THF) was added dropwise to (4-bromo-3-chlorophenoxy)(tert-butyl)dimethylsilane (le, 370 mg, 1.15 mmol) in THF (0.9 ml) at room température. After 3 h, the reaction was cooled to 0 °C and treated with 2-(3-oxoazetidin-l-yl)isonicotinonitrile (199 mg, 1.15 mmol) in one portion as a solid. After 1 h, the reaction was quenched with H2O and EtOAc. The organic layer was washed with brine, dried with Na2SO4 and concentrated. Purification by chromatography (ISCO 4 g silica column) using a gradient 100% hexanes -1:3 hexanes/EtOAc gave 2-(3-(4-((tertbutyldimethylsilyl)oxy)-2-chlorophenyl)-3-hydroxyazetidin-l-yl)isonicotinonitrile (Id).
Step 4: 2-(3-(2-ChIoro-4-hydroxyphenyl)-3-hydroxyazetidin-l-yl)isonicotinonitrile (le)
[0152] To a solution of 2-(3-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl)-3hydroxyazetidin-l-yl)isonicotinonitrile (Id) (180 mg, 0.43 mmol) in 2-MeTHF (4 mL) was added 1 M TBAF solution in THF (0.6 mL, 0.59 mmol) at room température. After 30 minutes, the mixture was quenched with water, extracted with EtOAc. The organic phase was washed with brine (10 mL), dried with Na2SO4, and concentrate to give 2-(3-(2-chloro-4hydroxyphenyl)-3-hydroxyazetidin-l-yl)isonicotinonitrile (le), which was used without further purification.
General Synthesis 2
Step 1: 2,6-dichloro-4-fluorobenzaldehyde oxime (2b)
[0153] A suspension of 2,6-dichloro-4-fluorobenzaldehyde (6.0 g, 31.2 mmol), NH2OH HCl (4.3g, 62.4 mmol), Na2CÜ3 (8.3g, 78.7 mmol) in ethanol-water (50 ml, 5:1) was stirred at room température for 3 h. The reaction was condensed under vacuum and the residue was treated with water followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, and concentrated to afford 2,6-dichloro-4-fluorobenzaldehyde oxime (2b).
Step 2: 2,6-dichloro-4-fliioro-N-hydroxybenzimidoyl chloride (2c)
[0154] To a solution of 2,6-dichloro-4-fluorobenzaldehyde oxime (2b, 5.5g, 26.7mmol) in DMF (10 mL) was added N-chlorosuccinimide (4.3 g, 32.0 mmol). The reaction was stirred at RT for 1 h. The mixture quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the 2,6-dichloro-4-fluoro-N-hydroxybenzimidoyl chloride (2c) that was used without further purification in the next step.
Step 3: ethyl 5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyI)isoxazole-4-carboxylate (2d)
[0155] To a solution of 3-cyclopropyl-3-oxo-propionic acid ethyl ester (5.0g, 32.0mmol) in 30 mL THF was added EtsN (10.8g, 107.2mmol), the reaction was stirred at RT for 30 min, then the reaction mixture from the previous step (2,6-dichloro-4-fluoro-N-hydroxybenzimidoyl chloride (2c)) was added dropwise. The resulting mixture was stirred for 2 h at RT. The solvent was removed and the residue was partitioned with 100 mL water and 50 mL EtOAc. The organic layer was washed with brine, dried, filtered, concentrated and purified by silica gel column (PE/EA=10/l) to give ethyl 5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazole-4carboxylate (2d).
Step 4: (5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4-yl)methanol (2e)
[0156] To the solution of ethyl 5 -cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazole-4carboxylate (2d, 3.4g, 9.3mmol) in THF (30ml) was added L1AIH4 (11.1ml, 11.1 mmol, 1 M in hexane) dropwise at 0 °C. The reaction was stirred for 30 min. 1.0 ml water was added, then 2.0 g 10% NaOH, 3.0 mL water were added. The mixture was filtered and concentrated. The crude was purified by silica gel column (PEZEA=2/1) to give (5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methanol (2e). LCMS (ESI): m/z 302.0 (M+l)+. ‘H NMR (500 MHz, CDCh): δ 7.22-7.20(d, J=8.5Hz, 2H), 4.42-4.41(d, J=6.0Hz, 2H), 2.19-2.16(m, 1H), 1.411.39(m, 1H), 1.29-1.26(m, 2H), 1.16-1.13(m, 2H).
General Synthesis 3
Step 1: methyl 5-fluoro-6-(3-hydroxyazetidin-l-yl)nicotinate (3a)
[0157] A mixture of azetidin-3-ol hydrochloride (2.8 g, 26 mmol), methyl 6-bromo-5fluoronicotinate (5.0 g, 21 mmol), and potassium carbonate (7.4 g, 53 mmol) in DMF (100 mL) was heated at 65 °C for 19 hours. The mixture was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI (m/z): [M+H]+ calcd for C10H12FN2O3: 227.1; found: 227.0.
Step 2: methyl 5-fhioro-6-(3-oxoazetidin-l-yl)nicotinate (3b)
[0158] A solution of methyl 5-fluoro-6-(3-hydroxyazetidin-l-yl)nicotinate (4.7 g, 21 mmol) in dichloromethane (270 mL) was treated with Dess-Martin periodinane (9.7 g, 23 mmol). After 6 hours of stirring at room température, an additional portion of Dess-Martin periodinane (1.5 g) was added, and the mixture was allowed to stir ovemight at room température. After stirring ovemight, the mixture was treated with aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnésium sulfate, filtered, concentrated to dryness under reduced pressure. The residue was purified twice by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H20+H]+ calcd for C10H12FN2O4: 243.1; found: 243.0.
Step 3: methyl 6-(3-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl)-3-hydroxyazetidin-lyl)-5-fluoronicotinate (3c)
[0159] A solution of (4-bromo-3-chlorophenoxy)(tert-butyl)dimethylsilane (4.5 g, 14 mmol) in 2-methyltetrahydrofuran (14 mL) was treated with isopropylmagnesium chloride/lithium chloride solution (Aldrich, 1,3M, 11 mL, 15 mmol) dropwise via syringe. The resulting mixture was stirred for approximately one hour and then was cooled in an ice-water bath. Methyl 5fluoro-6-(3-oxoazetidin-l-yl)nicotinate (2.0 g, 8.9 mmol) was added portions over 2 hours. The mixture was allowed to stand overnight at room température. The mixture was quenched with 10 % aqueous citric acid solution. The aqueous phase was extracted three times with ethyl acetate. The combined organics were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnésium sulfate, filtered, and concentrated under reduced pressure to provide the crude desired product which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H29C1FN2O4SÎ: 467.2; found: 467.1.
Step 4: methyl 6-(3-(2-cliloro-4-hydroxyphenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinate (3d)
[0160] Crude methyl 6-(3-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl)-3hydroxyazetidin-l-yl)-5-fluoronicotinate (approximately 10 mmol) was taken up in tetrahydrofuran (70 mL) and treated with tetra-n-butylammonium fluoride solution (Aldrich, 1.0 M in THF, 18 mL, 18 mmol). The mixture was allowed to stand at room température until deemed complété by LC/MS and then purified by flash chromatography (silica gel) to provide Intermediate 3d. LCMS-ESL (m/z): [M+H]+calcd for C16H15CIFN2O4: 353.1; found: 353.0.
Example 1: 5-((4-Bromo-3-chlorophenoxy)methyI)-4-cyclopropyl-l-(2,6-dichlorophenyl)IH-pyrazole
Step 1: 2,4-difluorobenzaldehyde oxime
[0161] This compound was synthesized according to the procedure as described in General Synthesis 2, Step 1 starting with 2,4-difluorobenzaldehyde (10 g, 70 mmol).
Step 2: 2,4-difluoro-N-hydroxybenzimidoyl chloride
[0162] This compound was synthesized according to the procedure as described in General Synthesis 2, Step 2 starting with 2,4-difluorobenzaldehyde oxime (9 g, 57 mmol).
Step 3: ethyl 5-cyclopropyl-3-(2,4-difluorophenyl)isoxazole-4-carboxylate
[0163] This compound was synthesized according to the procedure as described in General Synthesis 2, Step 3 starting with 2,4-difluoro-N-hydroxybenzimidoyl chloride (11 g, 57 mmol).
Step 4: (5-cyclopropyl-3-(2,4-difluorophenyl)isoxazol-4-yI)methanol
[0164] This compound was synthesized according to the procedure as described in General Synthesis 2, Step 4 starting with ethyl 5-cyclopropyl-3-(2,4-difluorophenyl)isoxazole-4carboxylate (2.2 g, 8 mmol).
Step 5: 4-(ChloromethyI)-5-cyclopropyl-3-(2,4-difluorophenyl)isoxazole
[0165] To a solution of (5-cyclopropyl-3-(2,4-difluorophenyl)isoxazol-4-yl)methanol (113 mg, 0.45 mmol) in CH2CI2 (2.3 mL) was added thionyl chloride (164 uL, 2.3 mmol) at 0 °C. The mixture was heated to reflux for 15 min and cooled to room température. The mixture was concentrated in vacuo. Additional CH2G2 (5 mL) was added and the mixture was concentrated again. This process was repeated a third time to remove excess thionyl chloride. The crude residue was used in the next step without further purification.
Step 6: 2-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,4-difhiorophenyI)isoxazol-4yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)isonicotinonitriIe
[0166] 4-(chloromethyl)-5-cyclopropyl-3-(2,4-difluorophenyl)isoxazole (113 mg, 0.45 mmol), 2-(3-(2-chloro-4-hydroxyphenyl)-3-hydroxyazetidin-l-yl)isonicotinonitrile (Intermediate le) (149 mg, 0.5 mmol) and K2CO3 (124 mg, 0.9 mmol) were combined in anhydrous DMF (2.3 mL) at room température. The mixture was heated to 65 °C under nitrogen. After 2 h, the solution was cooled to room température, quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by chromatography: ISCO (12g silica column) using a gradient of 100% CH2CI2- 3:1 CH2CI2/ premixed 60:35:5 CH2C12:Et2O:MeOH gave the title compound.
Step 7: 2-(3-(2-chloro-4-((5-cyclopropyI-3-(2,4-difluorophenyl)isoxazoI-4yI)methoxy)phenyl)-3-hydroxyazetidin-l-yl)isonicotinic acid (Example 1)
[0167] 10 M aqueous sodium hydroxide (0.67 ml) was added to 2-(3-(2-chloro-4-((5cyclopropyl-3-(2,4-difluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-lyl)isonicotinonitrile (210 mg, 0.39 mmol) in éthanol (2 mL) and H2O (2 mL) at room température and the mixture was heated at 60 °C for 90 minutes in a sealed tube. The mixture was cooled to room température and adjusted pH to about 5 with 1 M HCl which caused a precipitate to fall out of solution. The solution was filtered and the solid was rinsed with Et2O and dried in vacuo to give 2-(3-(2-chloro-4-((5-cyclopropyl-3-(2,4-difluorophenyl)isoxazol-4yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)isonicotinic acid (Example 1). *11 NMR (300 MHz, DMSO-dôVH NMR (300 MHz, DMSO-Jô) δ 13.41 (s, 1H), 8.19 (dd, J = 5.2, 0.8 Hz, 1H), 7.59 (td, 8.5, 6.5 Hz, 1H), 7.49 - 7.34 (m, 2H), 7.28 - 7.15 (m, 1H), 7.05 - 6.96 (m, 2H), 6.88 6.74 (m, 2H), 6.20 (s, 1H), 5.00 (s, 2H), 4.47 (d, J = 9.3 Hz, 2H), 4.18 (d, J = 9.2 Hz, 2H), 2.40 (tt, J = 8.3, 5.3 Hz, 1H), 1.20 - 1.00 (m, 4H). MS (ESI+) (m/z) 554.0 (M + H).
Example 2: 2-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyI)isoxazol-4yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)isonicotinic acid
Synthesis of Intermediate A:
[0168] To a solution of (4-bromo-3-chlorophenoxy)(tert-butyl)dimethylsilane (le, 60 g, 187 mmol) in THF (500 mL) was added dropwise n-BuLi (2.5 M, 75 mL) at -78 °C under N2. The reaction was stirred at -78 °C for 1 h. Next a solution of tert-butyl 3-oxoazetidine-l-carboxylate (27 g, 155 mmol) in THF (500 mL) was added dropwise to the mixture at -78 °C. Then the reaction was stirred at 20 °C for 3 h. The reaction mixture was poured into H2O (IL) and extracted with EtOAc (2 L) three times. The combined organic layers were washed with water (1 L), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluted with 10:1 petroleum ether:EtOAc to give 3-(4-((tert butyldimethylsilyl)oxy)-2-chlorophenyl)azetidin-3-ol (Intermediate A).
Step 1: terAbutyl 3-(2-chloro-4-hydroxyphenyI)-3-hydroxyazetidine-l-carboxylate
[0169] To a solution of terAbutyl 3-(4-((tert-butyldimethylsilyl)oxy)-2-chlorophenyl)-3hydroxyazetidine-l-carboxylate (Intermediate A, 1.27 g, 3.07 mmol) in THF (50.0 mL) at 10°C was added IM TB AF in THF (3.68 mL, 3.68 mmol) dropwise. The reaction was stirred for 2 hours and was concentrated to afford Ze/7-butyl 3-(2-chloro-4-hydroxyphenyl)-3hydroxyazetidine-1-carboxylate, which was used without further purification.
Step 2: 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazole
[0170] A solution of (5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4-yl)methanol (2e); 845 mg, 2.80 mmol) in DCM (28.0 mL) was cooled to 0°C. Thionyl chloride (1.02 mL, 14.0 mmol) was added and the solution was heated at 45 °C for 1 hour. The reaction was concentrated to dryness and used without purification in the next step.
Step 3: /ert-butyl 3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4yl)methoxy)phenyl)-3-hydroxyazetidine-l-carboxylate
[0171] A solution of teri-butyl 3-(2-chloro-4-hydroxyphenyl)-3-hydroxyazetidine-lcarboxylate (922 mg, 3.07 mmol) in DMF (28.0 mL) was added to crude 4-(chloromethyI)-5cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazole, followed by the addition of potassium carbonate (773 mg, 5.60 mmol). The mixture was heated at 60 °C for 8 hours. The reaction was concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried over MgSÜ4, filtered and concentrated. The crude product was purified by silica gel chromatography (DCM/EtoO/MeOH) to afford /e/7-butyl 3-(2-chloro4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3hydroxyazetidine-l-carboxylate. LCMS-ESI+ (m/z): [(M+H)-BOC] calcd 483.04; found 483.04.
Step 4: 3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyI)isoxazol-4yl)methoxy)phenyl)azetidin-3-ol
[0172] To a solution of Zert-butyl 3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidine-l-carboxylate (1.52 g, 2.60 mmol) in DCM (130 mL) was added 4 N HCl in 1,4-dioxane (26.0 mL, 104 mmol). The solution was stirred at room température for 2.5 hours and was concentrated to dryness to afford 3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4yl)methoxy)phenyl)azetidin-3-ol as the hydrochloride sait, which was used without further purification. LCMS-ESF (m/z): [M+H]+calcd 483.04; found 483.03.
Step 5: methyl 2-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4yI)methoxy)phenyl)-3-hydroxyazetidin-l-yl)isonicotmate
[0173] A mixture of methyl 2-bromopyridine-4-carboxylate (0.466 g, 2.16 mmol), 3-(2-chloro4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4-yl)methoxy)phenyl)azetidin-3-ol as the hydrochloride sait (1.02 g, 1.96 mmol), césium carbonate (2.56 g, 7.85 mmol), (±)-BINAP (0.244 g, 0.392 mmol), palladium acetate trimer (88.0 mg, 0.131 mmol) and 1,4-dioxane (40.0 mL) was heated at 85 °C for 18 hours. The reaction was cooled to room température, filtered over celite and purified by silica gel chromatography (acetone / hexanes) to afford methyl 2-(3(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3hydroxyazetidin-l-yl)isonicotinate. LCMS-ES1 (m/z): [M+H]+ calcd 618.08; found 618.20.
Step 6: 2-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4yI)methoxy)phenyl)-3-hydroxyazetidm-l-yl)isonicotinic acid (Example 2).
[0174] To a solution of 2-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l -yl)isonicotinate (617 mg, 0.997 mmol) in THF / water (1:1, 10 mL) was added lithium hydroxide monohydrate (83.6 mg, 1.99 mmol). The solution was stirred for 90 minutes, concentrated to remove THF and diluted with water. Acetic acid (0.23 mL, 3.99 mmol) was added while stirring which resulted in the précipitation of solids. The solids were filtered, washed with water, IPA and ether, and dried under vacuum to afford 2-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4 fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l -yl)isonicotinic acid (Example 2). LCMS-ESI+ (m/z): [M+H]+ calcd 604.06; found 604.15. ’H NMR (300 MHz, DMSO-ri6) δ 13.47 (br s, IH), 8.18 (dd, J= 5.3, 0.8 Hz, IH), 7.69 (d, J= 8.5 Hz, 2H), 7.37 (d, J= 8.7 Hz, IH), 7.02 (dd, J=5.3, 1.4 Hz, IH), 6.93 (d, J=2.6Hz, IH), 6.86 (br s, IH), 6.75 (dd, J=8.6, 2.6 Hz, IH), 6.20 (s, IH), 4.91 (s, 2H), 4.49 (d, 9.3 Hz, 2H), 4.19 (d, J= 9.3 Hz, 2H), 2.46 2.37 (m, IH), 1.23 - 1.04 (m, 4H).
Example 3: 6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyI)isoxazol-4yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid
[0175] Steps 1 -4 were as described for the synthesis of Example 2.
Step 5: methyl 6-(3-(2-ehloro-4-((5-cyclopropyI-3-(2,6-dichloro-4-fluorophenyI)isoxazoI-4yI)methoxy)phenyI)-3-hydroxyazetidm-l-yl)-5-fluoronicotinate
[0176] A mixture of methyl 6-chloro-5-fluoropyridine (235 mg, 1.24 mmol), 3-(2-chloro-4-((5cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4-yl)methoxy)phenyI)azetidin-3-ol as the hydrochloride sait (495 mg, 0.952 mmol) and potassium carbonate (1.05 g, 7.61 mmol) in DMF (30.0 mL) was heated at 60 °C for 1 hour. The reaction was concentrated, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by silica gel chromatography (DCM / Et2O / MeOH) to afford methyl 6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinate. LCMS-ESI+ (m/z): [M+H]+ calcd 636.07; found 635.96.
Step 6: 6-(3-(2-chIoro-4-((5-cycIopropyl-3-(2,6-dichloro-4-fluorophenyI)isoxazol-4yI)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid (Example 3)
[0177] To a solution of methyl 6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinate (364 mg, 0.571 mmol) in THF / water (1:1, 20.0 mL) was added lithium hydroxide monohydrate (41.3 mg, 0.984 mmol). The solution was stirred for 18 hours, concentrated to remove THF and diluted with water (10.0 mL). The pH was adjusted to 3 using IN HCl. The solids were filtered, washed with water, dissolved in ACN / water and lyophilized to afford 6-(3-(2-chloro-4-((5cyclopropyl-3-(2,6-dichloro-4-fluorophenyI)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidinl-yl)-5-fluoronicotinic acid (Example 3). LCMS-ESI+ (m/z): [Μ I H]+ calcd 622.05; found 622.12. Ή NMR (400 MHz, DMSO-d6) δ 12.84 (bs, 1H), 8.44 (t, J = 1.7 Hz, 1H), 7.79 - 7.63 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.6 Hz, 1H), 6.28 (s, 1H), 4.93 (s, 2H), 4.70 (d, J = 9.8 Hz, 2H), 4.34 (d, J = 9.5 Hz, 2H), 2.50-2.43 (m, 1H), 1.22 1.08 (m, 4H).
Intermediate 4: (3-(2,6-dichloro-4-fluorophenyl)-5-methylisoxazol-4-yl)methanol
[0178] Following General Synthesis 2, beginning with 2,6-dichloro-4-fluorobenzaldehyde in Step 1 and using ethyl acetoacetate in Step 3, (3-(2,6-dichloro-4-fluorophenyl)-5methylisoxazol-4-yl)methanol (Intermediate 4) was synthesized. LCMS-ESI+ (m/z): [M+H]+ calcd 276.00; found 276.05.
Example 4: Préparation of 6-(3-(2-chloro-4-((3-(2,6-dichloro-4-fluorophenyl)-5methylisoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid
F
F
[0179] Following the general procedure described for Example 3, using intermediate 4, 6-(3(2-chloro-4-((3-(2,6-dichloro-4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)phenyl)-3hydroxyazetidin-l-yl)-5-fluoronicotinic acid was synthesized. LCMS-ESI (m/z): [M+H]+ calcd 596.04; found 596.12. Ή NMR (400 MHz, DMSO-Jc) δ 12.82 (bs, 1H), 8.44 (t, J= 1.6 Hz, 1H), 7.74 —7.66 (m, 3H), 7.39 (d, J= 8.7 Hz, 1H), 6.90 (d, J=2.6Hz, 1H), 6.75 (dd, J=8.7, 2.6 Hz, 1H), 6.26 (s, 1H), 4.87 (s, 2H), 4.69 (d, J = 9.8 Hz, 2H), 4.34 (d, J = 9.8 Hz, 2H), 2.57 (s, 3H).
Example 5: 6-(3-(2-chloro-4-((4-cyclopropyl-l-(2,6-dichIoro-4-fluorophenyI)-lH-pyrazol-5yI)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid
Step 1: (2,6-dichloro-4-fluorophenyI)hydrazine hydrochloride
[0180] To a - 5 °C solution (internai température, wet ice/acetone bath) of 2,6-dichloro-4fluoroaniline (3.0 g, 17 mmol) in 37 % hydrochloric acid (30 mL) and trifluoroacetic acid (20 mL) was added dropwise an aqueous solution of sodium nitrite (1.4 g, 20 mmol, 6 mL water).
The reaction was stirred for 90 minutes, then a solution of stannous chloride dihydrate (5.6 g, 25 mmol) in 37 % hydrochloric acid (16 mL) was added over 15 minutes, keeping the internai température < 2 °C. The mixture was stirred ovemight at room température. The mixture was filtered and the collected solid was washed with isopropyl alcohol and dried under house vacuum to provide the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C6H6CI2FN2: 195.0; found: 194.9.
Step 2: ethyl 4-cyclopropyl-l-(2,6-dichloro-4-fhiorophenyl)-lH-pyrazole-5-carboxylate
[0181] Ν,Ν-Dimethylformamide dhnethyl acetal (2.7 mL, 20 mmol) was added to ethyl 3cyclopropyl-2-oxopropanoate (Synnovator, 1.6 g, 10 mmol) and stirred ovemight at room température. The mixture was then concentrated to dryness under reduced pressure. To the residue was added successively éthanol (40 mL), (2,6-dichloro-4-fluorophenyl)hydrazine hydrochloride (2.6 g, 11 mmol), and 37 % hydrochloric acid (150 pL). The reaction was stirred at room température for four hours, followed by 2 days of heating at reflux. The cooled mixture was purified by flash chromatography (silica gel) to provide the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H14CI2FN2O2: 343.0; found: 343.1.
Step 3: (4-cyclopropyl-l-(2,6-dichloro-4-fluorophenyl)-lH-pyrazol-5-yl)methanol
[0182] A solution of ethyl 4-cyclopropyl-l -(2,6-dichloro-4-fluorophenyl)-l H-pyrazole-5carboxylate (1.5 g, 4.4 mmol) in tetrahydrofuran (50 mL) was cooled to between -12 and -10 °C. A solution of lithium aluminum hydride (Aldrich, 2 M in tetrahydrofuran, 2.6 mL, 5.2 mmol) was added dropwise. The mixture was allowed to stir for 35 minutes. The mixture was quenched (Fieser procedure) and purified by flash chromatography (silica gel) to provide the title compound. LCMS-ESfl (m/z): [M+H]+ calcd for Ci3Hi2C12FN2O: 301.0; found: 301.1.
Step 4: 5-(chloromethyl)-4-cyclopropyl-l-(2,6-dichloro-4-fluorophenyl)-lH-pyrazole
[0183] Thionyl chloride (110 pL, 1.5 mmol) was added to a solution of (4-cyclopropyl-l-(2,6dichloro-4-fluorophenyl)-lH-pyrazol-5-yl)methanol (0.15 g, 0.51 mmol) in dichloromethane (2.5 mL). The mixture was heated at 60 °C for 40 minutes and then concentrated under reduced pressure to provide the crude desired product, which was carried forward without further purification. LCMS-ESfl (m/z): [M+Hfl calcd for C13H11CI3FN2: 319.0; found: 319.1.
Step 5: methyl 6-(3-(2-chloro-4-((4-cyclopropyl-l-(2,6-dichloro-4-fluorophenyl)-lHpyrazol-5-yl)methoxy)phenyl)-3-hydroxyazetidm-l-yl)-5-fliioronicotinate
[0184] A solution of 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazole (0.16 g, 0.51 mmol) in DMF (3 mL) was treated with methyl 6-(3-(2-chloro-4-hydroxyphenyl)3-hydroxyazetidin-l-yl)-5-fluoronicotinate (0.20 g, 0.56 mmol), sodium iodide (0.13 g, 0.86 mmol), and potassium carbonate (0.14 g, 1.0 mmol). The mixture was heated 65 °C overnight and then purified by flash chromatography (silica gel) to provide the desired material. LCMSESI+ (m/z): [M+Hf calcd for C29H24CI3F2N4O4: 635.1; found: 635.2.
Step 6: 6-(3-(2-chloro-4-((4-cyclopropyl-l-(2,6-dichloro-4-fluorophenyl)-lH-pyrazol-5yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid (Example 5)
[0185] A mixture of methyl 6-(3-(2-chloro-4-((4-cyclopropyl-l-(2,6-dichloro-4-fluorophenyl)IH-pyrazol-5-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinate (0.35 g, 0.39 mmol) and lithium hydroxide monohydrate (49 mg, 1.2 mmol) were taken up in 1:1 aqueous tetrahydrofuran (6 mL), and the mixture was stirred at room température. Upon completion, the mixture was acidifîed with glacial acetic acid and concentrated. The residue was purified by flash chromatography (silica gel) to provide 6-(3-(2-chloro-4-((4-cyclopropyl-l-(2,6-dichloro-4fluorophenyl)-lH-pyrazol-5-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid (Example 5). LCMS-ESL (m/z): [M+H]+ calcd for C28H22CI3F2N4O4: 621.1; found: 621.2. 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.44 (t, J = 1.6 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 12.7, 1.7 Hz, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.80 (dd, J = 8.7, 2.6 Hz, 1H), 6.28 (s, 1H), 5.01 (s, 2H), 4.69 (d, J - 9.8 Hz, 2H), 4.34 (d, J = 9.6 Hz, 2H), 1.89 (tt, J = 8.4, 5.1 Hz, 1H), 0.93 (m, 2H), 0.65 (m, 2H).
Example 6: 5-((15,35)-3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyI)-3-hydroxycyclobutyl)-6-methoxynicotmic acid
Synthesis of Intermediate 5
Step 1: (5-bromo-6-methoxypyridin-3-yl)methanol
[0186] To a solution of methyl 5-bromo-6-methoxynicotinate (52.8 g, 215.0 mmol) in THF (500 mL) was added DIBAL-H (1.0 M, in toluene) (344 ml, 344 mmol) at -20°C. Then the mixture was stirred at RT for 2 h. The mixture was quenched with sat. NH4C1 and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, fiitered, concentrated under reduced pressure and purified by flash chromatography on silica gel (ΡΕ/EtOAc = 4/1 ) to give the title compound.
Step 2: 3-bromo-5-(((tert-butyldimethyIsilyl)oxy)methyl)-2-methoxypyridine
[0187] To a solution of (5-bromo-6-methoxypyridin-3-yl)methanol (42.2 g, 194 mmol) and tert-butyldimethylsilyl chloride (35.0 g, 232mmol) in CH2CI2 (500 ml) was added imidazole (19.8 g, 291 mmol). The mixture was stirred at RT for 8 h. The mixture was quenched with water and diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (PE/EtOAc = 10/1) to give the titie compound.
Step 3: 3-(benzyloxy)-l-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridin-3yl)cyclobutan-l-ol
[0188] 3-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methoxypyridine (61.2 g, 184 mmol) was dissolved in absolute THF (500 mL) under argon,) a 1.6 M solution of n-butyllithium (138 mL, 221 mmol) in THF was added dropwise at -78°C. The mixture was stirred for 30 min at the same température. A solution of 3-(benzyloxy)cyclobutan-l-one (35.7 g, 202mmol) in THF (100 mL) was then added at -78° C, and the mixture was subsequently stirred at this température for 30 min. Saturated aqueous ammonium chloride was subsequently added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnésium sulfate and filtered. After removal of the solvent on a rotary evaporator, the residue was purified by flash chromatography on silica gel (PE/EtOAc = 2/1 ) to give the titie compound.
Step 4: 3-(benzyloxy)-l-(5-(hydroxymethyl)-2-methoxypyridin-3-yl)cycIobutan-l-ol
[0189] To a solution of 3-(benzyloxy)-l-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2methoxypyridin-3-yl)cyclobutan-l-ol (31.6 g, 73.6mmol) in THF (300mL) was added TBAF (88 mL, 1 mol/L). The mixture was stirred at rt for 6 hours, then poured into water and extracted with ethyi acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnésium sulfate and filtered. The organic phase was concentrated to give the titie compound.
Step 5: 5-(3-(benzyloxy)-l-hydroxycyclobutyl)-6-methoxynicotinic acid
[0190] To a solution of 3-(benzyloxy)-l-(5-(hydroxymethyl)-2-methoxypyridin-3yl)cyclobutan-l-ol (23.2 g, 73.6 mmol) in MeCN (300 mL) and H2O (100 mL) was added iodobenzene diacetate (64.4 g, 200mmol) and TEMPO (7.86g, 50 mmol), and the solution was stirred at room température for 2 hrs. The mixture was quenched with sat. sodium bicarbonate solution and diluted with ethyi acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered; the organic phase was concentrated to give the titie compound.
Step 6: methyl 5-(3-(benzyloxy)-l-hydroxycyclobutyl)-6- methoxynicotinate
[0191] To a solution of 5-(3-(benzyloxy)-l-hydroxycyclobutyl)-6-methoxynicotinic acid (17.5g, crude) in THF/MeOH (200/50 mL) was added TMSN2CH3 (50 mL, 20 mol/L) at 0 °C.
The mixture was stirred at room température for 3 hours, then poured into water and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnésium sulfate and filtered. The fîltrate was concentrated under reduced pressure and purified by flash chromatography on silica gel (PE/EA=10.1) to give the title compound.
Step 7: methyl 5-(3-(benzyloxy)-l-fluorocyclobutyl)-6-methoxynicotinate
[0192] To a cooled solution of methyl 5-(3-(benzyloxy)-l-hydroxycyclobutyl)-6methoxynicotinate (15.2g, 44.3 mmol) in DCM (200mL) was added DAST (8.0 mL) at -78°C dropwise by syringe. After stirring 5 minutes at -78° C, the reaction was allowed to warm to -20° C. and stirred for 75 minutes, then it was quenched with H2O (100 mL) , diluted with EtOAc and the phases were separated. The organic phase was washed with sat. aq. NaHCOs and brine, then dried over MgSO i, filtered, and concentrated. The crude product was purified by chromatography (PE: EtOAc=4:l) to give the title compound.
Step 8: methyl 5-(3-hydroxycyclobutyl)-6-methoxynicotinate
[0193] To a solution of methyl 5-(3-(benzyloxy)-l-fluorocyclobutyl)-6-methoxynicotinate (12.7 g, 3.68 mmol) in MeOH (200 mL) and formic acid (10 mL) was added Pd black (3.0 g). The reaction was stirred vigorously under N2. After about 1.5 hrs, additional Pd black was added (1.5 g) and the reaction stirred ovemight. The reaction mixture was filtered and concentrated.
The residue was dissolved in EtOAc and washed with sat. Na2CÜ3. The organic phase was dried over MgSÛ4, filtered and concentrated to an oily residue. The residue was purified by chromatography (MeOH: CH2Ch= 1:20) to give the title compound.
Step 9: methyl 6-methoxy-5-(3-oxocyclobutyl)nicotinate (Intermediate 5) o ,— /OH o __
[0194] To a solution of methyl 5-(3-hydroxycyclobutyl)-6-methoxynicotinate (4.0 g, 16.9 mmol) in MeCN (100 mL) and H2O (30 mL) was added iodobenzene diacetate (16.1 g, 50 mmol) and TEMPO (2.92 g, 18.6 mmol), and the solution was stirred at room température for 2 hrs. The mixture was quenched with sat. Na2CO3 and then diluted with ethyl acetate. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and purified by chromatography (PE: EA= 5:1) to give Intermediate 5.
Step 10: 4-((4-bromo-3-chlorophenoxy)methyl)-5-cyclopropyI-3-(2,6-dichloro-4fhiorophenyl)isoxazole
[0195] A solution of crude 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazole (prepared as described in Example 2, step 2; 0.42 g, 1.3 mmol) in N,Ndimethylformamide (DMF, 6 mL) was treated with 4-bromo-3-chlorophenol (0.27 g, 1.3 mmol), sodium iodide (0.34 g, 2.2 mmol), and potassium carbonate (0.37 g, 2.6 mmol). The mixture was heated at 60 °C for 35 minutes before it was cooled and purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for Ci9Hi3BrCl3FNO2: 491.9; found: 492.0.
Step 11: Methyl 5-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol4-yl)methoxy)phenyI)-3-hydroxycyclobutyl)-6-methoxynicotinate
[0196] Under an atmosphère of Argon, a solution of 4-((4-bromo-3-chlorophenoxy)methyl)-5cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazole (0.83 g, 1.7 mmmol) in 2methyltetrahydrofuran (2 mL) was treated with isopropylmagnesium chloride/lithium chloride solution (Aldrich, 1.3 M in tetrahydrofuran, 1.3 mL, 1.7 mmol) dropwise via syringe. After the passage of four hours, an additional volume of isopropylmagnesium chloride/lithium chloride solution (1.3 mL) was added. In a separate vessel, under an atmosphère of Argon, a solution of methyl 6-methoxy-5-(3-oxocyclobutyl)nicotinate (Intermediate 5), 0.21 g, 0.90 mmol) in tetrahydrofuran (5 mL) was treated with lanthanum (ΠΙ) chloride/2 lithium chloride solution (Aldrich, 0.6 M in tetrahydrofuran, 1.5 mL, 0.9 mmol). This mixture was stirred for one hour at room température before it was cooled in a -8 °C wet ice/acetone bath. The Grignard solution from above was added dropwise to the ketone solution via syringe. The reaction mixture was stirred overnight under an Argon atmosphère. The mixture was quenched with saturated aqueous ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The combined organics were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnésium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the titie compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H27CI3FN2O6: 647.1; found: 647.1.
Step 12: 5-((15',3»S)-3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fliiorophenyI)isoxazoI4-yl)methoxy)phenyl)-3-hydroxycyclobiityl)-6-methoxynicotmic acid (Example 6)
[0197] A mixture of methyl 5-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxycyclobutyl)-6-methoxynicotinate (0.26 g, 0.40 mmol) and lithium hydroxide monohydrate (33 mg, 0.79 mmol) were taken up in 1:1 aqueous tetrahydrofuran (10 mL) and stirred overnight at room température. The volatiles were mostly removed by under reduced pressure. The aqueous mixture was diluted with water and treated dropwise with 10 % aqueous hydrochloric acid. The resulting mixture was extracted with ethyl acetate three times. The combined organics were washed with saturated aqueous sodium chloride solution (with a small amount of hydrochloric acid added). The combined organics were dried over anhydrous magnésium sulfate, filtered, and concentrated under reduced pressure. The residue was purified first by flash chromatography (silica gel) and then by préparative HPLC (acetonitrile/water, TFA). The combined fractions collected by HPLC were neutralized with saturated aqueous sodium hydrogen carbonate solution, saturated with sodium chloride, and extracted three times with ethyl acetate. The combined organics were dried over anhydrous magnésium sulfate, filtered, and concentrated. The residue was taken up in ethyl acetate, treated with anhydrous magnésium sulfate, filtered, and concentrated. Again the residue was taken up in ethyl acetate and filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to provide 5-((1Χ,30)-3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxycyclobutyl)-6-methoxynicotinic acid (Example 6). LCMS-ESr (m/z): [M+H]+ calcd for C30H25CI3FN2O6: 633.1; found: 633.1. 1H NMR (400 MHz, DMSO-d6) δ 13.00 (bs, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 2.3, 0.8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 8.7, 2.6 Hz, 1H), 4.94 (s, 2H), 3.90 (s, 3H), 3.15-3.03 (m, 2H), 2.91 (p, J = 8.8 Hz, 1H), 2.49 - 2.41 (m, 1H), 2.41 - 2.30 (m, 2H), 1.21 - 1.09 (m, 4H).
Example 7: 2-(6-(3-(2-chloro-4-((5-cycIopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4yl)methoxy)phenyl)-3-hydroxyazetidm-l-yI)-5-fluoronicotinamido)ethane-l-sulfonic acid
[0198] A solution of 6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid (Example 3, 0.11 g, 0.18 mmol) in DMF (4 mL) was treated with HATU (1 [bis(dirnethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 0.10 g, 0.27 mmol) followed by taurine (34 mg, 0.27 mmol) and N,N-diisopropylethylamine (90 pL, 0.54 mmol). The mixture was stirred ovemight at room température and was then purified by préparative HPLC (water/acetonitrile/TFA). The combined fractions were treated with ammonium hydroxide solution and concentrated to give 2-(6-(3-(2-chloro-4-((5-cyclopropyl-3(2,6-dichloro-4-fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3 -hydroxyazetidin-1 -yl)-5 fluoronicotinamido)ethane-l-sulfonic acid (Example 7) as the ammonium sait. LCMS-ESl (m/z): [M+H]+ calcd for C30H26CI3F2N4O7S: 729.1; found: 729.2. ‘H NMR (400 MHz, DMSOd6) δ 8.34 (m, 2H), 7.73 - 7.61 (m, 3H), 7.37 (d, J = 8.6 Hz, 1H), 7.29 - 6.95 (m, 4H), 6.92 (d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.6, 2.5 Hz, 1H), 6.22 (s, 1H), 4.90 (s, 2H), 4.63 (d, J = 9.6 Hz, 2H), 4.29 (d, J = 9.6 Hz, 2H), 3.46 (q, J = 6.5 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.45 - 2.38 (m, 1H), 1.16 (dt, J = 8.5, 3.1 Hz, 2H), 1.10 (dt, J = 5.4, 2.9 Hz, 2H).
Example 8: (6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazol-4yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinoyl)glycine
Step 1: methyl (6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichIoro-4-fluorophenyl)isoxazol-4yI)methoxy)phenyI)-3-hydroxyazetidin-l-yl)-5-fluoronicotinoyl)glycinate
[0199] A solution of 6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinic acid (Example 3, 0.12 g, 0.19 mmol) in DMF (4 mL) was treated with HATU (1[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridmium 3-oxid hexafluorophosphate, 0.11 g, 0.29 mmol) followed by glycine methyl ester hydrochloride (36 mg, 0.29 mmol) and N,N-diisopropylethylamine (100 uL, 0.58 mmol). The mixture was stirred ovemight at room température and was then quenched with saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once with 1:1 saturated aqueous sodium chloride solution/saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnésium sulfate, filtered, and concentrated under reduced pressure to give the desired product, which was carried forward without further purification. LCMS-ESL (m/z): [M+H] calcd for C31H26CI3F2N4O6: 693.1; found: 693.2.
Step 2: (6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4-fluorophenyl)isoxazoI-4yI)methoxy)phenyl)-3-hydroxyazetidin-l-yI)-5-fIuoronicotinoyl)gIycine (Example 8)
[0200] A mixture of crude methyl (6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5fluoronicotinoyl)glycinate (approximately 0.19 mmol) and lithium hydroxide monohydrate (38 mg, 0.91 mmol) in aqueous tetrahydrofuran (2:1, 3 mL) was stirred at room température for 3.5 hours. The volatile solvent was removed under reduced pressure. The residue was diluted with water and acidified to pH 1 with 10 % aqueous hydrochloric acid. The acidic aqueous mixture was extracted three times with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnésium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide (6-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichloro-4fluorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-l-yl)-5-fluoronicotinoyl)glycine (Example 8). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H24CI3F2N4O6: 679.1; found: 679.3. Ή NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.68 (t, J = 5.8 Hz, 1H), 8.44 (t, J = 1.7 Hz, 1H), 7.80 (dd, J = 13.2, 1.8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.6 Hz, 1H), 6.26 (s, 1H), 4.93 (s, 2H), 4.66 (d, J = 9.5 Hz, 2H), 4.32 (d, J = 9.3 Hz, 2H), 3.87 (d, J = 5.8 Hz, 2H), 2.48 - 2.42 (partially obscured by DMSO, m, 1H), 1.16 (m,4H).
Example 9: FRET activity assay
[0201] Détermination of a ligand mediated cofactor peptide interaction to quantify ligand binding to the nuclear receptor FXR was performed as follows.
[0202] Préparation of human FXR alpha ligand binding domain: The human FXRalpha LBD was expressed in E. coli strain BL21(DE3) as an N-terminally GST tagged fusion protein. The DNA encoding the FXR ligand binding domain was cloned into vector pDEST15 (Invitrogen). Expression was under control of an IPTG inducible T7 promoter. The amino acid boundaries of the ligand binding domain were amino acids 187-472 of Database entry NM_005123 (RefSeq). Expression and purification of the FXR-LBD: An overnight preculture of a transformed E.coli strain was diiuted 1:20 in LB-Ampicillin medium and grown at 30°C to an optical density of ODsoo=0.4-0.6. Gene expression was then induced by addition of 0.5 mM IPTG. Cells were incubated an additional 6 h at 30°C, 180 rpm. Cells were collected by centrifugation (7000 x g, 7 min, rt). Per liter of original cell culture, cells were resuspended in 10 mL lysis buffer (50 mM Glucose, 50 mM Tris pH 7.9, 1 mM EDTA and 4 mg/mL lysozyme) and left on ice for 30 min. Cells were then subjected to sonication and cell débris removed via centrifugation (22000 x g, 30 min, 4 °C). Per 10 mL of supematant 0.5 mL prewashed Glutathione 4B sepharose slurry (Qiagen) was added and the suspension kept slowly rotating for 1 h at 4 °C. Glutathione 4B sepharose beads were pelleted by centrifugation (2000 x g, 15 sec, 4 °C) and washed twice in wash buffer (25 mM Tris, 50 mM KC1, 4 mM MgCk and IM NaCl). The pellet was resuspended in 3 mL elution buffer per liter of original culture (elution buffer: 20 mM Tris, 60 mM KC1, 5 mM MgCL and 80 mM glutathione added immediately prior to use as powder). The suspension was left rotating for 15 min at 4 °C, the beads pelleted and eluted again with half the volume of elution buffer than the first time. The eluates were pooled and dialysed ovemight in 20 mM Hepes buffer (pH 7.5) containing 60 mM KO, 5 mM MgCh as well as 1 mM dithiothreitol and 10% (v/v) glycerol. The protein was analysed by SDS-Page.
[0203] The method measures the ability of putative ligands to modulate the interaction between the purified bacterial expressed FXR ligand binding domain (LBD) and a synthetic biotinylated peptide based on residues 676-700 of SRC-1 (LCD2, 676-700). The sequence of the peptide used was B-CPSSHSSLTERHKILHRLLQEGSPS-COOH (SEQ ID NO: 1) where the Nterminus was biotinylated (B). The ligand binding domain (LBD) of FXR was expressed as fusion protein with GST in BL-21 cells using the vector pDEST15. Cells were lysed by somcation, and the fusion proteins purified over glutathione sepharose (Pharmacia) according to the manufacturers instructions. For screening of compounds for their influence on the FXRpeptide interaction, the Perkin Elmer LANCE technology was applied. This method relies on the binding dépendent energy transfer from a donor to an accepter fluorophor attached to the binding partner of interest. For ease of handling and réduction of background from compound fluorescence LANCE technology makes use of generic fluorophore labels and time resolved détection Assays were done in a final volume of 25 pL in a 384 well plate, in a Tris-based buffer (20 mM Tris-HCl pH 7.5; 60 mM KG, 5 mM MgCL; 35 ng/pL BSA), containing 20-60 ng/well recombinantly expressed FXR-LBD fused to GST, 200-600 nM N-terminally biotinylated peptide, representing SRC1 aminoacids 676-700, 200 ng/well Streptavidin-xlAPC conjugate(Prozyme) and 6—10 ng/well Eu W1024 - antiGST (Perkin Elmer). DMSO content of the samples was kept at 1%. After génération of the assay mix and diluting the potentially FXR modulating ligands, the assay was equilibrated for 1 h in the dark at rt in FIA-plates black 384 well (Greiner). The LANCE signal was detected by a Perkin Elmer VICTOR2VTM Multilabel Counter. The results were visualized by plotting the ratio between the emitted light at 665 and 615 nm. A basal level of FXR-peptide formation is observed in the absence of added ligand. Ligands that promote the complex formation induce a concentration-dependent increase in time resolved fluorescent signal. Compounds which bind equally well to both monomeric FXR and to the FXR-peptide complex would be expected to give no change in signal, whereas ligands which bind preferentially to the monomeric receptor would be expected to induce a concentrationdependent decrease in the observed signal.
[0204] To assess the agonistic potential of the compounds, ECso values were determined for example compounds and are listed below in Table 2 (FRET ECso).
Example 10: Mammalian one hybrid (M1H) assay
[0205] Détermination of a ligand mediated Gal4 promoter driven transactivation to quantify ligand binding mediated activation of FXR was performed as follows.
[0206] The cDNA part encoding the FXR ligand binding domain was cloned into vector pCMV-BD (Stratagene) as a fusion to the yeast GAL4 DNA binding domain under the control of the CMV promoter. The amino acid boundaries of the ligand binding domain were amino acids 187-472 of Database entry NM_005123 (RefSeq). The plasmid pFR-Luc (Stratagene) was used as the reporter plasmid, containing a synthetic promoter with five tandem repeats of the yeast GAL4 binding sites, driving the expression of the Photinus pyralis (American firefly) luciferase gene as the reporter gene. In order to improve experimental accuracy the plasmid pRL-CMV (Promega) was cotransfected. pRL-CMV contains the constitutive CMV promoter, controlling the expression of the Renifla reniformis luciferase. Ail Gal4 reporter gene assays were done in HEK293 cells (obtained from DSMZ, Braunschweig, Germany) grown in MEM with LGlutamine and Earle's BSS supplemented with 10% fêtai bovine sérum, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, and 100 units Penicilin/Streptavidin per mL at 37 °C in 5% CO2. Medium and suppléments were obtained from Invitrogen. For the assay, 5 x 105 cells were plated per well in 96 well plates in 100 gL per well MEM without Phénol Red and L-Glutamine and with Earle's BSS supplemented with 10% charcoal/dextran treated FBS (HyClone, South Logan, Utah), 0.1 mM nonessential amino acids, 2 mM glutamine, 1 mM sodium pyruvate, and 100 units Penicilin/ Streptavidin per mL, incubated at 37 °C in 5% CO2. The following day the cells were >90% confluence. Medium was removed and cells were transiently transfected using 20 gL per well of an OptiMEM - polyethylene-imine-based transfection-reagent (OptiMEM, Invitrogen; Polyethyleneimine, Aldrich Cat No. 40,827-7) including the three plasmids described above. MEM with the same composition as used for plating cells was added 2-4 h after addition of transfection mixture. Then compound stocks, prediluted in MEM were added (final vehicle concentration not exceeding 0.1%). Cells were incubated for additional 16 h before fîrefly and renilla luciferase activities were measured sequentially in the same cell extract using a DualLight-Luciferase-Assay System (Dyer et al., Anal. Biochem. 2000, 282, 158-161). Ail experiments were done in triplicates.
[0207] To assess the FXR agonistic potency of the example compounds, potency was determined in the Ml H assay and is listed below in Table 2 (Ml H EC50).
Table 2
Example | FRET ECso (nM) | MlHEC5o(nM) |
1 | 263 | 3000 |
2 | 25 | 831 |
3 | 7.4 | 3.8 |
4 | 35 | 176 |
5 | 18 | 8.6 |
6 | 49 | 353 |
7 | 6.9 | 1696 |
8 | 8.1 | 1264 |
Example 11: Métabolite ID assay in human liver microsomes
[0208] The metabolic stability of Example 3 and Comparative Example 1 in human liver microsmoes was conducted according to the following procedure. Human liver microsomes (35 pL protein concentration 20 mg/mL), 350 pL of 100 mM potassium phosphate buffer (pH 7.4), 245 pL of deionized water and 0.7 pL of compound stock solution (5mM) were combined in a 1.5 mL microcentrifuge tube. The tube was sealed and gently vortexed for 10 seconds, then placed in an Eppendorf ThermoMixer C and pre-warmed at 37 °C with shaking at 1100 rpm for 5 minutes.
[0209] NADPH solution (70 pL; 10 mM in water) was added while shaking, the mixture was aspirated several times with pipet, and 200 pLwas removed to a fresh 1.5 mL microcentrifuge tube on ice containing 200 pL of cold acetonitrile. This aliquot was vortexed at high speed for 10 seconds then placed on ice. After 30 and 60 minutes additional 200 pl aliquots were removed and transferred to fresh 1.5 mL microcentrifuge tube on ice containing 200 pL of cold acetonitrile. These were vortexed at high speed for 10 seconds then placed on ice.
[0210] The chilled aliquots were centrifuged at 14,300 rpm in a microcentrifuge for 10 minutes at 10 °C, then the supematant was transferred to a deepwell (1 mL) 96 well plate and sealed with a Silicon mat. The sample was transferred to the Cool Stack of the autoinjector (température set to 10 °C) and 20 pL was injected into the Thermo Elite Orbitrap mass spectrometer. 20 pL samples were analyzed by UPLC-MS in order to identify and quantify the métabolites (Agilent 1290 G4220 binary pump UPLC with Agilent G1316 TCC column oven; Waters Acquity UPLC BEH C18 (130 Â pore size, 1.7 pm particle size, 2.1 x 50 mm) column held at 40 °C; Agilent 1290 G4212 DAD diode array with wavelength range 190 to 400 nm; Thermo Electron Orbitrap Elite mass spectrometer in FTMS positive mode).
[0211] Final microsomal protein concentration: 1 mg/mL
[0212] Final NADPH concentration: 1 mM
[0213] Final substrate concentration: 5 pM
[0214] Time points: 0, 30, 60 minutes
[0215] Incubation volume per time point: 200 pL
[0216] Comparative Example 1, a direct comparator to Example 3 that lacks a 4fluorophenyl substituent présent in the compounds disclosed herein, was found to be metabolized to a diol compound (Ml) under the conditions described above (Scheme 1). Incorporation of the 4-fluoro substituent inhibited formation of métabolite Ml under the same conditions.
Scheme 1
Comparative Example 1 m/z 604.0610
OH
M1 m/z 638.0664 Abundance by UV 23%
Example 3 m/z 622.0512
M1
M/Z 638.0664 Abundance by UV <1%
Example 12: Assessment of In Vivo Pharmacodynamies in Cynomolgus Monkey
[0217] In vivo pharmacodynamies of a représentative compound of Formula (I) and a comparative example compound were determined as follows.
[0218] Test Article and Formulation
[0219] Oral suspension doses of a représentative compound of Formula (I) (Example 3) and Comparative Example 2 (Example 13/9 of U.S. Patent No. 9,139,539) were formulated at concentrations of 2, 6, 20, and 60 mg/mL in aqueous suspensions of 0.5% sodium carboxymethylcellulose (Na CMC), 1% éthanol, and 98.5% 50mM Tris buffer, at pH 8.
[0220] Animais
[0221] Each dosing group consisted of three male Cynomolgus monkeys. At dosing, the animais weighed between 2.5 and 4.4 kg.
[0222] Dosing
[0223] The test articles were administered to the monkeys via oral gavage at 5 mL/kg. Prior to withdrawal, the gavage tube was flushed with approximately 10 mL of water.
[0224] Sample Collection
[0225] Venous blood samples were taken at specified time points after dosing from each animal. The blood samples were collected and transferred into tubes containing potassium (K2) EDTA anticoagulant.
[0226] Détermination of FGF19 Concentrations in Plasma
[0227] The FGF19 ELIS A assay kit from BioVendor (product number RDI 91107200R) was used to détermine FGF19 concentrations in the collected blood samples.
[0228] Détermination of Drug Concentratsion in Plasma
[0229] An aliquot of 50 pL of each plasma sample from the 10 and 30 mg/kg dosing groups and the t = 0 samples from the 100 and 300 mg/kg groups were treated with 200 pL of acetonitrile (ACN) containing internai standard. An aliquot of 25 pL of the remaining samples from the 100 mg/kg group was combined with 25 pL of blank plasma to effect a 1:2 dilution and treated with 200 pL of acetonitrile (ACN) containing internai standard. An aliquot of 10 pL of the remaining samples from the 300 mg/kg group was combined with 40 pL of blank plasma to effect a 1:5 dilution and treated with 200 pL of acetonitrile (ACN) containing internai standard. The above solutions were centrifuged at 5000 RPM for 10 minutes and 50 pL of supematant was transferred to a clean 96-well plate, followed by the addition of 200 pL of water. An aliquot of 10 pL was injected to the API 5000 LC/MS/MS System. Samples exceeding the calibration range of the instrument were diluted and re-analyzed.
[0230] HPLC Conditions
[0231] A Zorbax Extend C18 HPLC column (50 x 2.1 mm, 3.5 p) from Agilent Technologies (Part # 735700-902) was used. Mobile phase A contained an aqueous solution of 1% acetonitrile in 10 mM ammonium formate adjusted to pH 3.0 with formic acid. Mobile phase B contained and 10% 10 mM ammonium formate in acetonitrile adjusted to pH 5.2 with formic acid. A Thermo Aria multiplexer with two identical Agilent 1200 sériés binary pumps (P/N G1312A Bin Pump) was used for elution and séparation. The elution program used is set forth in the following Table 3.
Table 3.
Time (sec) | Step Comments | Flow Rate (mL/min) | Mobile Phase A (%) | Mobile Phase B (%) |
30 | Sample Loading | 0.50 | 85 | 15 |
180 | Ramp | 0.50 | 50 | 50 |
90 | Ramp | 0.50 | 99 | 1 |
60 | Elution | 0.50 | 99 | 1 |
120 | Re-equilibrium | 0.50 | 85 | 15 |
[0232] An API 5000 triple quadrupole mass spectrometer from AB Sciex, Foster City, CA was used in multiple reaction monitoring mode to quantify the compounds. The mass spectrometry parameters used are set forth in the following Table 4.
Table 4.
Ion source | Spray voltage (V) | Gas 1 (Arb) | Gas 2 (Arb) | Collision gas (Arb) | Dryer température (°C) |
Turbo Ion Spray | 5500 | 70 | 50 | 6 | 550 |
[0233] Results
FGF 19 levels were compared following oral administration of increasing doses of Example 3 or Comparative Example 2 (3 to 300 mg/kg). Dose-dependent increases in plasma exposure were observed for both compounds and the maximal AUC achieved with each compound at 300mg/kg were comparable (Figure 1 ). Example 3 dose-dependently increased plasma FGF19, reaching a Cmax of 16000 pg/ml at the highest dose (Figure 2). Administration of Comparative Example 2 also caused increases in plasma FGF19, but the maximal level of FGF19 was significantly lower (Cmax 3000 ng/ml) than for Example 3. Furthermore, maximal FGF 19 induction by Comparative Example 2 was achieved at 5 mg/kg; higher doses provided no further increase despite greater plasma drug exposures (Figure 2). This Example demonstrates that IV or oral administration of Example 3 can induce greater FGF19 levels than Comparative Example 2.
* * *
[0234] Unless otherwise defined, ail techmcal and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0235] Thus, it should be understood that although the présent disclosure has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation ofthe disclosures embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are représentative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.
[0236] The disclosure has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the generic disclosure also form part ofthe disclosure. This includes the generic description ofthe disclosure with a proviso or négative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.
[0237] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.
[0238] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.
Claims (19)
1. A compound according to Formula (la):
wherein:
Q is phenylene substituted with one chloro;
R1 is cyclopropyl or methyl;
R2 and R3 are chloro;
R4
R4-A is:
, wherein the pyridylene is optionally substituted with one or two groups independently selected from halogen, Ci-4-alkoxy, halo-Ci-4-alkoxy, Ci-4-alkyl, and haloCi-4-alkyl;
R4 is -CO2R5 or -C(O)NR5R6;
R5 is hydrogen; and
R6 is Ci-2-alkyl optionally substituted with -SO3H, or -CO2H;
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
2. The compound of claim 1, wherein A is pyridylene substituted with one fluoro; or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
3. The compound of claim 1, wherein A is unsubstituted pyridylene; or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
4. The compound of any one of claims 1-3, wherein R4 is -CO2R5, and R5 is hydrogen; or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
5. The compound of any one of claims 1-3, wherein:
R4 is -C(O)NR5R6;
R5 is hydrogen; and
R6 is Ci-2-alkyl, wherein said Ci-2-alkyl is substituted with -SO3H or -CO2H;
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
6. The compound of claim 1 wherein R4-A is:
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
7. A compound selected from the group consisting of:
or a pharmaceutically acceptable sait, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof.
8. A compound having the following formula:
or a pharmaceutically acceptable sait thereof.
9. A compound having the following formula:
F
10. A pharmaceutical composition comprising a compound or pharmaceutically acceptable sait of any one of claims 1-9 and a pharmaceutically acceptable excipient.
11. Use of a compound or pharmaceutically acceptable sait thereof of any one of claims 1-9 or a pharmaceutical composition of claim 10 in the manufacture of a médicament for treating a patient having an FXR mediated condition.
12. The use of claim 11, wherein the FXR mediated condition is selected from the group consisting of:
a chronic intrahepatic or some form of extrahepatic cholestatic condition;
liver fibrosis;
an obstructive inflammatory disorder of the liver;
chronic inflammatory disorder of the liver;
liver cirrhosis;
liver steatosis or an associated syndrome;
cholestatic or fibrotic effects that are associated with alcohol-induced cirrhosis or with viral-bome forms of hepatitis;
liver failure or liver ischemia after major liver resection;
chemotherapy associated steatohepatitis (CASH);
acute liver failure; and
Inflammatory Bowel Disease.
13. The use of claim 11, wherein the FXR mediated condition is selected from the group consisting of:
a lipid and lipoprotein disorder;
Type I Diabètes;
Type II Diabètes;
clinical complications of Type I and Type II Diabètes selected from the group consisting of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other observed effects of clinically manifest long term Diabètes;
Non-Alcoholic Fatty Liver Disease (NAFLD);
Non-Alcoholic Steatohepatitis (NASH);
Primary Biliary Cirrhosis (PBC);
Primary Scelrosing Cholangitis (PSC);
obesity;
a metabolic syndrome selected from the group consisting of combined conditions of dyslipidemia, diabètes and abnormally high body-mass index;
acute myocardial infarction;
acute stroke; and thrombosis which occurs as an endpoint of chronic obstructive atherosclerosis.
14. The use of claim 11, wherein the FXR mediated condition is selected from the group consisting of:
a non-malignant hyperproliferative disorder; and a malignant hyperproliferative disorder selected from the group consisting of hepatocellular carcinoma, colon adenoma, and polyposis;
colon adenocarcinoma;
breast cancer;
pancréas adenocarcinoma;
Barrett's esophagus; and other forms of neoplastic diseases of the gastrointestinal tract and the liver.
15. A compound or pharmaceutically acceptable sait thereof of any one of claims 1-9, or a pharmaceutical composition of claim 10, for use in the treatment of a FXR mediated condition.
16. The compound or pharmaceutically acceptable sait of claim 15, or the pharmaceutical composition of claim 15, wherein the FXR mediated condition is Non-Alcoholic Steatohepatitis (NASH).
17. The use of claim 13, wherein the FXR mediated condition is Non-Alcoholic Steatohepatitis (NASH).
18. The use of claim 13, wherein the FXR-mediated condition is Primary Biliary Cirrhosis (PBC).
19. The use of claim 13, wherein the FXR-mediated condition is Primary Sclerosing Cholangitis (PSC).
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62/349,490 | 2016-06-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA19551A true OA19551A (en) | 2020-12-11 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2021254625B2 (en) | FXR (NR1H4) modulating compounds | |
AU2017284160B2 (en) | FXR (NR1H4) modulating compounds | |
US20220204491A1 (en) | Fxr (nr1h4) modulating compounds | |
OA19551A (en) | FXR (NR1H4) modulating compounds. | |
OA20099A (en) | "FXR (NR1H4) modulating compounds". |