JP5114395B2 - Gpcrアゴニスト - Google Patents
Gpcrアゴニスト Download PDFInfo
- Publication number
- JP5114395B2 JP5114395B2 JP2008520006A JP2008520006A JP5114395B2 JP 5114395 B2 JP5114395 B2 JP 5114395B2 JP 2008520006 A JP2008520006 A JP 2008520006A JP 2008520006 A JP2008520006 A JP 2008520006A JP 5114395 B2 JP5114395 B2 JP 5114395B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- mmol
- compounds
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229940125633 GPCR agonist Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 235
- 150000003839 salts Chemical class 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 208000008589 Obesity Diseases 0.000 claims description 22
- 235000020824 obesity Nutrition 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 206010012601 diabetes mellitus Diseases 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 10
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 6
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 6
- 230000036186 satiety Effects 0.000 claims description 6
- 235000019627 satiety Nutrition 0.000 claims description 6
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 5
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 5
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 4
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- 239000000203 mixture Substances 0.000 description 89
- 238000000034 method Methods 0.000 description 80
- 239000000243 solution Substances 0.000 description 77
- 239000002904 solvent Substances 0.000 description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- -1 chloro, methyl Chemical group 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 235000019439 ethyl acetate Nutrition 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 34
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 34
- 238000002360 preparation method Methods 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000012267 brine Substances 0.000 description 29
- 238000004440 column chromatography Methods 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- 238000003756 stirring Methods 0.000 description 28
- 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 23
- 229920006395 saturated elastomer Polymers 0.000 description 23
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 22
- 125000005843 halogen group Chemical group 0.000 description 22
- 229910052727 yttrium Inorganic materials 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- 125000001072 heteroaryl group Chemical group 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- 229910052721 tungsten Inorganic materials 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 125000003709 fluoroalkyl group Chemical group 0.000 description 16
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 16
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 101000996752 Homo sapiens Glucose-dependent insulinotropic receptor Proteins 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000008194 pharmaceutical composition Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 239000000883 anti-obesity agent Substances 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 11
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 11
- 102100033839 Glucose-dependent insulinotropic receptor Human genes 0.000 description 11
- 102000004877 Insulin Human genes 0.000 description 11
- 108090001061 Insulin Proteins 0.000 description 11
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 11
- 229940125710 antiobesity agent Drugs 0.000 description 11
- 229940095074 cyclic amp Drugs 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 229940125396 insulin Drugs 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 10
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000006185 dispersion Substances 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012312 sodium hydride Substances 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 210000005253 yeast cell Anatomy 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000000556 agonist Substances 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 125000001153 fluoro group Chemical group F* 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000002480 mineral oil Substances 0.000 description 7
- 235000010446 mineral oil Nutrition 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 230000003000 nontoxic effect Effects 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- JOMWMDCZYGEZKT-UHFFFAOYSA-N tert-butyl 4-[(2z)-2-amino-2-hydroxyiminoethoxy]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OCC(=N)NO)CC1 JOMWMDCZYGEZKT-UHFFFAOYSA-N 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 5
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 210000000577 adipose tissue Anatomy 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000011734 sodium Chemical class 0.000 description 5
- 150000003457 sulfones Chemical group 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 4
- FAOCTKCDCODWIP-UHFFFAOYSA-N 5-chloro-3-(4-methylsulfonylphenyl)-1,2,4-oxadiazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=NOC(Cl)=N1 FAOCTKCDCODWIP-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 238000013262 cAMP assay Methods 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 230000003914 insulin secretion Effects 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 4
- 150000003462 sulfoxides Chemical group 0.000 description 4
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 4
- 239000012414 tert-butyl nitrite Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 150000003568 thioethers Chemical class 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- WAIWHRUQKRUWAH-UHFFFAOYSA-N 2-fluoro-4-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)C(F)=C1 WAIWHRUQKRUWAH-UHFFFAOYSA-N 0.000 description 3
- ZTOBILYWTYHOJB-WBCGDKOGSA-N 3',6'-bis[[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy]spiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CC=C2C3(C4=CC=CC=C4C(=O)O3)C3=CC=C(O[C@H]4[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O4)O)C=C3OC2=C1 ZTOBILYWTYHOJB-WBCGDKOGSA-N 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- FDUGOYTWYJZNNP-UHFFFAOYSA-N 4-amino-2-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C(F)=C1 FDUGOYTWYJZNNP-UHFFFAOYSA-N 0.000 description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013065 commercial product Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 230000001603 reducing effect Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000000825 ultraviolet detection Methods 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- IXCYVKHRSWQORD-UHFFFAOYSA-N 1-(4-cyclopropylsulfanylphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1SC1CC1 IXCYVKHRSWQORD-UHFFFAOYSA-N 0.000 description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 2
- HZFMOHIBTBOZRU-UHFFFAOYSA-N 1-azido-4-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=C(N=[N+]=[N-])C=C1 HZFMOHIBTBOZRU-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- YHUAHIMRWSVXCN-UHFFFAOYSA-N 2-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxyacetic acid Chemical compound CC(C)(C)OC(=O)N1CCC(OCC(O)=O)CC1 YHUAHIMRWSVXCN-UHFFFAOYSA-N 0.000 description 2
- PGFIHORVILKHIA-UHFFFAOYSA-N 2-bromopyrimidine Chemical compound BrC1=NC=CC=N1 PGFIHORVILKHIA-UHFFFAOYSA-N 0.000 description 2
- VDQPQADDCPAAEX-UHFFFAOYSA-N 2-fluoro-4-methylsulfonylbenzamide Chemical compound CS(=O)(=O)C1=CC=C(C(N)=O)C(F)=C1 VDQPQADDCPAAEX-UHFFFAOYSA-N 0.000 description 2
- WBQJZAVZWHEYQU-UHFFFAOYSA-N 3-(4-methylsulfonylphenyl)-2h-1,2,4-oxadiazol-5-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=NOC(O)=N1 WBQJZAVZWHEYQU-UHFFFAOYSA-N 0.000 description 2
- MGRHBBRSAFPBIN-UHFFFAOYSA-N 3-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C=C1F MGRHBBRSAFPBIN-UHFFFAOYSA-N 0.000 description 2
- 125000006164 6-membered heteroaryl group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100026189 Beta-galactosidase Human genes 0.000 description 2
- 101100064718 Borrelia bavariensis (strain ATCC BAA-2496 / DSM 23469 / PBi) fusA1 gene Proteins 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229940124802 CB1 antagonist Drugs 0.000 description 2
- 101100209555 Caenorhabditis elegans vha-17 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-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
- 108020004414 DNA Proteins 0.000 description 2
- 208000030814 Eating disease Diseases 0.000 description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940100607 GPR119 agonist Drugs 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 108050006759 Pancreatic lipases Proteins 0.000 description 2
- 102000019280 Pancreatic lipases Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229940127003 anti-diabetic drug Drugs 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 108010005774 beta-Galactosidase Proteins 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 235000019577 caloric intake Nutrition 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 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 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 235000014632 disordered eating Nutrition 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005283 haloketone group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 102000056352 human GPR119 Human genes 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940039781 leptin Drugs 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Chemical class 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229940116369 pancreatic lipase Drugs 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000011591 potassium Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 2
- 230000000862 serotonergic effect Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- HXRDRJKAEYHOBB-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(CO)C1 HXRDRJKAEYHOBB-UHFFFAOYSA-N 0.000 description 2
- AXFHYLRXARSNKA-UHFFFAOYSA-N tert-butyl 4-(2-amino-2-oxoethoxy)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OCC(N)=O)CC1 AXFHYLRXARSNKA-UHFFFAOYSA-N 0.000 description 2
- QBKIYLAAMXUGDA-UHFFFAOYSA-N tert-butyl 4-(cyanomethoxy)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OCC#N)CC1 QBKIYLAAMXUGDA-UHFFFAOYSA-N 0.000 description 2
- IMILYTVDGBXCAE-UHFFFAOYSA-N tert-butyl 4-[[3-(3-fluoro-4-methylsulfonylphenyl)-1,2,4-oxadiazol-5-yl]methoxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OCC1=NC(C=2C=C(F)C(=CC=2)S(C)(=O)=O)=NO1 IMILYTVDGBXCAE-UHFFFAOYSA-N 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
- 238000012360 testing method Methods 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- COKYDRZCLUZJJA-UHFFFAOYSA-N (1-methylcyclobutyl) piperidine-1-carboxylate Chemical compound CC1(CCC1)OC(=O)N1CCCCC1 COKYDRZCLUZJJA-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MIAKOEWBCMPCQR-YBXAARCKSA-N (2s,3r,4s,5r,6r)-2-(4-aminophenoxy)-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound C1=CC(N)=CC=C1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MIAKOEWBCMPCQR-YBXAARCKSA-N 0.000 description 1
- AXJQVVLKUYCICH-OAQYLSRUSA-N (4s)-5-(4-chlorophenyl)-n-(4-chlorophenyl)sulfonyl-n'-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide Chemical compound C=1C=C(Cl)C=CC=1C([C@H](C1)C=2C=CC=CC=2)=NN1C(=NC)NS(=O)(=O)C1=CC=C(Cl)C=C1 AXJQVVLKUYCICH-OAQYLSRUSA-N 0.000 description 1
- HKHTWSLPCGOYJA-OAQYLSRUSA-N (4s)-5-(4-chlorophenyl)-n-(4-chlorophenyl)sulfonyl-n-methyl-4-phenyl-3,4-dihydropyrazole-2-carboxamide Chemical compound C=1([C@H](CN(N=1)C(=O)N(C)S(=O)(=O)C=1C=CC(Cl)=CC=1)C=1C=CC=CC=1)C1=CC=C(Cl)C=C1 HKHTWSLPCGOYJA-OAQYLSRUSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XTIGGAHUZJWQMD-UHFFFAOYSA-N 1-chloro-2-methoxyethane Chemical compound COCCCl XTIGGAHUZJWQMD-UHFFFAOYSA-N 0.000 description 1
- DPJHZJGAGIWXTD-UHFFFAOYSA-N 1-fluoro-4-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=C(F)C=C1 DPJHZJGAGIWXTD-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- DQWVUKFABWSFJD-UHFFFAOYSA-N 1-methylcyclobutan-1-ol Chemical compound CC1(O)CCC1 DQWVUKFABWSFJD-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- AKAMNXFLKYKFOJ-UHFFFAOYSA-N 2,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1F AKAMNXFLKYKFOJ-UHFFFAOYSA-N 0.000 description 1
- TYBODNNAYBREIC-UHFFFAOYSA-N 2,5-difluoro-4-methylsulfanylbenzoic acid Chemical compound CSC1=CC(F)=C(C(O)=O)C=C1F TYBODNNAYBREIC-UHFFFAOYSA-N 0.000 description 1
- HTJXSYFJLGCUBL-UHFFFAOYSA-N 2-[[1-[(2-methylpropan-2-yl)oxycarbonyl]azetidin-3-yl]methoxy]acetic acid Chemical compound CC(C)(C)OC(=O)N1CC(COCC(O)=O)C1 HTJXSYFJLGCUBL-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- ZRXQHWYUAIXKRL-UHFFFAOYSA-N 2-bromo-5-methylsulfonylpyridine Chemical compound CS(=O)(=O)C1=CC=C(Br)N=C1 ZRXQHWYUAIXKRL-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- GXBXPURGSKUHHB-UHFFFAOYSA-N 2-fluoro-1-methyl-4-methylsulfanylbenzene Chemical compound CSC1=CC=C(C)C(F)=C1 GXBXPURGSKUHHB-UHFFFAOYSA-N 0.000 description 1
- LKZYNWBZLPDDII-UHFFFAOYSA-N 2-fluoro-4-methylsulfanylbenzonitrile Chemical compound CSC1=CC=C(C#N)C(F)=C1 LKZYNWBZLPDDII-UHFFFAOYSA-N 0.000 description 1
- UHNSRUQBYCAURK-UHFFFAOYSA-N 2-fluoro-4-methylsulfonylbenzonitrile Chemical compound CS(=O)(=O)C1=CC=C(C#N)C(F)=C1 UHNSRUQBYCAURK-UHFFFAOYSA-N 0.000 description 1
- UXBIHGQYRYAMFN-UHFFFAOYSA-N 2-fluoro-4-nitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=C(C#N)C(F)=C1 UXBIHGQYRYAMFN-UHFFFAOYSA-N 0.000 description 1
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- DOHPCRULOPVJFL-UHFFFAOYSA-N 2-tert-butyl-4-hydroxypiperidine-1-carboxylic acid Chemical compound CC(C)(C)C1CC(O)CCN1C(O)=O DOHPCRULOPVJFL-UHFFFAOYSA-N 0.000 description 1
- NLAVHUUABUFSIG-UHFFFAOYSA-N 3,4,5-trifluorobenzaldehyde Chemical compound FC1=CC(C=O)=CC(F)=C1F NLAVHUUABUFSIG-UHFFFAOYSA-N 0.000 description 1
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 description 1
- PGMIRFQOAYOMFF-UHFFFAOYSA-N 3,5-difluoro-4-methylsulfanylbenzaldehyde Chemical compound CSC1=C(F)C=C(C=O)C=C1F PGMIRFQOAYOMFF-UHFFFAOYSA-N 0.000 description 1
- CAYYTTZRKZPRCS-UHFFFAOYSA-N 3,5-difluoro-4-methylsulfanylbenzonitrile Chemical compound CSC1=C(F)C=C(C#N)C=C1F CAYYTTZRKZPRCS-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- YMGADXXOTWPYBL-UHFFFAOYSA-N 3-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxypropanoic acid Chemical compound CC(C)(C)OC(=O)N1CCC(OCCC(O)=O)CC1 YMGADXXOTWPYBL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- VAHXXQJJZKBZDX-UHFFFAOYSA-N 3-chloro-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1Cl VAHXXQJJZKBZDX-UHFFFAOYSA-N 0.000 description 1
- MOTAJJVUNNOUSO-UHFFFAOYSA-N 3-chloro-4-methylsulfanylbenzonitrile Chemical compound CSC1=CC=C(C#N)C=C1Cl MOTAJJVUNNOUSO-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- JMHGATOBRPWPBZ-UHFFFAOYSA-N 3-cyano-4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(C#N)=C1 JMHGATOBRPWPBZ-UHFFFAOYSA-N 0.000 description 1
- WZMUVXIXRLICBM-UHFFFAOYSA-N 3-fluoro-4-methylsulfanylbenzaldehyde Chemical compound CSC1=CC=C(C=O)C=C1F WZMUVXIXRLICBM-UHFFFAOYSA-N 0.000 description 1
- NATGKFYJHRNRHO-UHFFFAOYSA-N 3-fluoro-4-methylsulfanylbenzonitrile Chemical compound CSC1=CC=C(C#N)C=C1F NATGKFYJHRNRHO-UHFFFAOYSA-N 0.000 description 1
- RUJPQBWSTIZQAD-UHFFFAOYSA-N 3-fluoro-4-methylsulfinylbenzoic acid Chemical compound CS(=O)C1=CC=C(C(O)=O)C=C1F RUJPQBWSTIZQAD-UHFFFAOYSA-N 0.000 description 1
- QJHFDGZWRWQZCR-UHFFFAOYSA-N 3-fluoro-4-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)C=C1F QJHFDGZWRWQZCR-UHFFFAOYSA-N 0.000 description 1
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 1
- LLIHOORDCCKQRR-UHFFFAOYSA-N 4-(bromomethyl)-1-(4-methylsulfonylphenyl)pyrazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1N=CC(CBr)=C1 LLIHOORDCCKQRR-UHFFFAOYSA-N 0.000 description 1
- XFDVQBHPFMGRPQ-UHFFFAOYSA-N 4-(bromomethyl)-1-(4-methylsulfonylphenyl)triazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1N=NC(CBr)=C1 XFDVQBHPFMGRPQ-UHFFFAOYSA-N 0.000 description 1
- UIPKZLABRKFIBG-UHFFFAOYSA-N 4-(chloromethyl)-1-(4-methylsulfonylphenyl)pyrazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1N=CC(CCl)=C1 UIPKZLABRKFIBG-UHFFFAOYSA-N 0.000 description 1
- IOCYEPKKGLLCRJ-UHFFFAOYSA-N 4-(chloromethyl)-1-(4-methylsulfonylphenyl)triazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1N=NC(CCl)=C1 IOCYEPKKGLLCRJ-UHFFFAOYSA-N 0.000 description 1
- SSQYTNKIPVKEJW-UHFFFAOYSA-N 4-[3-[[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxymethyl]-1,2,4-oxadiazol-5-yl]benzoic acid Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OCC1=NOC(C=2C=CC(=CC=2)C(O)=O)=N1 SSQYTNKIPVKEJW-UHFFFAOYSA-N 0.000 description 1
- TZHBGEGWFBEPCR-UHFFFAOYSA-N 4-[5-(4-pentylcyclohexyl)-1,2,4-oxadiazol-3-yl]aniline Chemical compound C1CC(CCCCC)CCC1C1=NC(C=2C=CC(N)=CC=2)=NO1 TZHBGEGWFBEPCR-UHFFFAOYSA-N 0.000 description 1
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 1
- IWTYCLUZCZNVMY-UHFFFAOYSA-N 4-chlorooxadiazole Chemical compound ClC1=CON=N1 IWTYCLUZCZNVMY-UHFFFAOYSA-N 0.000 description 1
- YBIJTPAZFNXOAW-UHFFFAOYSA-N 4-cyano-2-fluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(C#N)C=C1F YBIJTPAZFNXOAW-UHFFFAOYSA-N 0.000 description 1
- UYHVZXCIAQVHMY-UHFFFAOYSA-N 4-cyano-2-fluorobenzenesulfonyl chloride Chemical compound FC1=CC(C#N)=CC=C1S(Cl)(=O)=O UYHVZXCIAQVHMY-UHFFFAOYSA-N 0.000 description 1
- KEJMSTJTAWACNI-UHFFFAOYSA-N 4-cyano-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(C#N)C=C1F KEJMSTJTAWACNI-UHFFFAOYSA-N 0.000 description 1
- FQFXHZATRHYKCE-UHFFFAOYSA-N 4-cyclopropylsulfanylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1SC1CC1 FQFXHZATRHYKCE-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 description 1
- XJEVFFNOMKXBLU-UHFFFAOYSA-N 4-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=C(N)C=C1 XJEVFFNOMKXBLU-UHFFFAOYSA-N 0.000 description 1
- AJBWNNKDUMXZLM-UHFFFAOYSA-N 4-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)C=C1 AJBWNNKDUMXZLM-UHFFFAOYSA-N 0.000 description 1
- ZYJCSKAGKUQLQK-UHFFFAOYSA-N 4-pentylcyclohexane-1-carbonitrile Chemical compound CCCCCC1CCC(C#N)CC1 ZYJCSKAGKUQLQK-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- ZDUBEUYONKELDS-UHFFFAOYSA-N 5-(4-methylsulfonylphenyl)-3-[(1-pyrimidin-2-ylpiperidin-4-yl)oxymethyl]-1,2,4-oxadiazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=NC(COC2CCN(CC2)C=2N=CC=CN=2)=NO1 ZDUBEUYONKELDS-UHFFFAOYSA-N 0.000 description 1
- JDRQJLLHNFNMER-UHFFFAOYSA-N 5-(chloromethyl)-1-(4-methylsulfonylphenyl)triazole Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1C(CCl)=CN=N1 JDRQJLLHNFNMER-UHFFFAOYSA-N 0.000 description 1
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 102100031933 Adhesion G protein-coupled receptor F5 Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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
- 238000003276 AlphaScreen cAMP assay kit Methods 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LVRCEUVOXCJYSV-UHFFFAOYSA-N CN(C)S(=O)=O Chemical compound CN(C)S(=O)=O LVRCEUVOXCJYSV-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 102000004859 Cholecystokinin Receptors Human genes 0.000 description 1
- 108090001085 Cholecystokinin Receptors Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102100032165 Corticotropin-releasing factor-binding protein Human genes 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 102000038624 GSKs Human genes 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 229940123935 Galanin receptor agonist Drugs 0.000 description 1
- 102100031416 Gastric triacylglycerol lipase Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class 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 1
- 229940121931 Gluconeogenesis inhibitor Drugs 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000007390 Glycogen Phosphorylase Human genes 0.000 description 1
- 108010046163 Glycogen Phosphorylase Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101000775045 Homo sapiens Adhesion G protein-coupled receptor F5 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000015580 Increased body weight Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910009891 LiAc Inorganic materials 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 229940122142 Lipoxygenase inhibitor Drugs 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical class [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 108010008364 Melanocortins Proteins 0.000 description 1
- 101710151321 Melanostatin Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 101100069093 Mus musculus Gpr119 gene Proteins 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102400000064 Neuropeptide Y Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 229940124754 PPAR-alpha/gamma agonist Drugs 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 229940121908 Retinoid X receptor agonist Drugs 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 241001474728 Satyrodes eurydice Species 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 description 1
- 229940123659 Sorbitol dehydrogenase inhibitor Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Tetrahydrothiophene-1,1-dioxide, Natural products O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000007984 Tris EDTA buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- DGYKJVWNECWJKJ-UHFFFAOYSA-N [1-(4-methylsulfonylphenyl)pyrazol-4-yl]methanol Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1N=CC(CO)=C1 DGYKJVWNECWJKJ-UHFFFAOYSA-N 0.000 description 1
- YZSOWZBXYYAVEC-UHFFFAOYSA-N [1-(4-methylsulfonylphenyl)triazol-4-yl]methanol Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1N=NC(CO)=C1 YZSOWZBXYYAVEC-UHFFFAOYSA-N 0.000 description 1
- ZDUKFQPGLJUKSW-UHFFFAOYSA-N [3-(4-methylsulfonylphenyl)triazol-4-yl]methanol Chemical compound C1=CC(S(=O)(=O)C)=CC=C1N1C(CO)=CN=N1 ZDUKFQPGLJUKSW-UHFFFAOYSA-N 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
- 150000004703 alkoxides Chemical group 0.000 description 1
- 125000005275 alkylenearyl group Chemical group 0.000 description 1
- 125000005218 alkyleneheteroaryl group Chemical group 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001409 amidines Chemical group 0.000 description 1
- 150000001411 amidrazones Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 238000012440 amplified luminescent proximity homogeneous assay Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003243 anti-lipolytic effect Effects 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 208000029162 bladder disease Diseases 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 108010083720 corticotropin releasing factor-binding protein Proteins 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- YIBKCPJOFAUAKY-UHFFFAOYSA-N cyclopropylsulfanylbenzene Chemical compound C1CC1SC1=CC=CC=C1 YIBKCPJOFAUAKY-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000020805 dietary restrictions Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000004212 difluorophenyl group Chemical group 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000002621 endocannabinoid Substances 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- MPIFOHPRCJZLQS-UHFFFAOYSA-N ethyl 1-(4-methylsulfonylphenyl)pyrazole-4-carboxylate Chemical compound C1=C(C(=O)OCC)C=NN1C1=CC=C(S(C)(=O)=O)C=C1 MPIFOHPRCJZLQS-UHFFFAOYSA-N 0.000 description 1
- UFEHGPVVTRPMKY-UHFFFAOYSA-N ethyl 5-methylsulfonylpyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC=C(S(C)(=O)=O)C=N1 UFEHGPVVTRPMKY-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108010091264 gastric triacylglycerol lipase Proteins 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 229940126013 glucocorticoid receptor antagonist Drugs 0.000 description 1
- 239000003850 glucocorticoid receptor antagonist Substances 0.000 description 1
- 229940124828 glucokinase activator Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 108010093115 growth factor-activatable Na-H exchanger NHE-1 Proteins 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000742 histaminergic effect Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000012528 insulin ELISA Methods 0.000 description 1
- 239000011872 intimate mixture Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229940045996 isethionic acid 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
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002865 melanocortin Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- WHJMGBFVYCLTFS-UHFFFAOYSA-N methyl 2,4,5-trifluorobenzoate Chemical compound COC(=O)C1=CC(F)=C(F)C=C1F WHJMGBFVYCLTFS-UHFFFAOYSA-N 0.000 description 1
- ZBWQGTMONIZZFB-UHFFFAOYSA-N methyl 2,5-difluoro-4-methylsulfanylbenzoate Chemical compound COC(=O)C1=CC(F)=C(SC)C=C1F ZBWQGTMONIZZFB-UHFFFAOYSA-N 0.000 description 1
- RYJSFYBJYKFNCF-UHFFFAOYSA-N methyl 3-cyano-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(C#N)=C1 RYJSFYBJYKFNCF-UHFFFAOYSA-N 0.000 description 1
- SDGNQBGXYYIYLC-UHFFFAOYSA-N methyl 4-(methoxymethylsulfanyl)benzoate Chemical compound COCSC1=CC=C(C(=O)OC)C=C1 SDGNQBGXYYIYLC-UHFFFAOYSA-N 0.000 description 1
- BTSFXVSAECXZNJ-UHFFFAOYSA-N methyl 4-cyano-2-fluorobenzoate Chemical compound COC(=O)C1=CC=C(C#N)C=C1F BTSFXVSAECXZNJ-UHFFFAOYSA-N 0.000 description 1
- BTZOMWXSWVOOHG-UHFFFAOYSA-N methyl 4-sulfanylbenzoate Chemical compound COC(=O)C1=CC=C(S)C=C1 BTZOMWXSWVOOHG-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000014925 multi-organism signaling Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- FERZLTOGCPKONO-UHFFFAOYSA-N n'-hydroxy-4-methylsulfanylbenzenecarboximidamide Chemical compound CSC1=CC=C(C(N)=NO)C=C1 FERZLTOGCPKONO-UHFFFAOYSA-N 0.000 description 1
- ASVKDPCGOIIZIN-UHFFFAOYSA-N n'-hydroxy-4-methylsulfonylbenzenecarboximidamide Chemical compound CS(=O)(=O)C1=CC=C(C(\N)=N\O)C=C1 ASVKDPCGOIIZIN-UHFFFAOYSA-N 0.000 description 1
- HICLOAWZZHOSEC-UHFFFAOYSA-N n-[(3,5-difluoro-4-methylsulfanylphenyl)methylidene]hydroxylamine Chemical compound CSC1=C(F)C=C(C=NO)C=C1F HICLOAWZZHOSEC-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000000406 opioidergic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940080358 other antiobesity drug in atc Drugs 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical group C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 235000014483 powder concentrate Nutrition 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000013630 prepared media Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009892 regulation of energy homeostasis Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011781 sodium selenite Substances 0.000 description 1
- 229960001471 sodium selenite Drugs 0.000 description 1
- 235000015921 sodium selenite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AGDSCTQQXMDDCV-UHFFFAOYSA-M sodium;2-iodoacetate Chemical compound [Na+].[O-]C(=O)CI AGDSCTQQXMDDCV-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YBNJZIDYXCGAPX-UHFFFAOYSA-N tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCO)CC1 YBNJZIDYXCGAPX-UHFFFAOYSA-N 0.000 description 1
- PSRHRFNKESVOEL-UHFFFAOYSA-N tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC=O)CC1 PSRHRFNKESVOEL-UHFFFAOYSA-N 0.000 description 1
- UHRUOFKUBQRCQV-UHFFFAOYSA-N tert-butyl 4-(3-ethoxy-1-hydroxy-3-oxopropyl)piperidine-1-carboxylate Chemical compound CCOC(=O)CC(O)C1CCN(C(=O)OC(C)(C)C)CC1 UHRUOFKUBQRCQV-UHFFFAOYSA-N 0.000 description 1
- CWTULLANCDLMGK-UHFFFAOYSA-N tert-butyl 4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate Chemical compound CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 CWTULLANCDLMGK-UHFFFAOYSA-N 0.000 description 1
- PAWONGOVVNXTDP-UHFFFAOYSA-N tert-butyl 4-[2-(methylamino)ethyl]piperidine-1-carboxylate Chemical compound CNCCC1CCN(C(=O)OC(C)(C)C)CC1 PAWONGOVVNXTDP-UHFFFAOYSA-N 0.000 description 1
- IRWIROIBXUYQND-UHFFFAOYSA-N tert-butyl 4-[2-[[3-(4-methylsulfonylphenyl)-1,2,4-oxadiazol-5-yl]oxy]ethyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CCOC1=NC(C=2C=CC(=CC=2)S(C)(=O)=O)=NO1 IRWIROIBXUYQND-UHFFFAOYSA-N 0.000 description 1
- ZPCJOEJTRYUMGU-UHFFFAOYSA-N tert-butyl 4-[[1-(4-methylsulfonylphenyl)pyrazol-4-yl]methoxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OCC1=CN(C=2C=CC(=CC=2)S(C)(=O)=O)N=C1 ZPCJOEJTRYUMGU-UHFFFAOYSA-N 0.000 description 1
- GUPWKCBERNMJSG-UHFFFAOYSA-N tert-butyl 4-[[3-[3-(2-hydroxyethylamino)-4-methylsulfonylphenyl]-1,2,4-oxadiazol-5-yl]methoxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OCC1=NC(C=2C=C(NCCO)C(=CC=2)S(C)(=O)=O)=NO1 GUPWKCBERNMJSG-UHFFFAOYSA-N 0.000 description 1
- JLKMGRSXFPZDCQ-UHFFFAOYSA-N tert-butyl 4-[[3-[3-fluoro-4-(2-hydroxyethylsulfanyl)phenyl]-1,2,4-oxadiazol-5-yl]methoxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OCC1=NC(C=2C=C(F)C(SCCO)=CC=2)=NO1 JLKMGRSXFPZDCQ-UHFFFAOYSA-N 0.000 description 1
- YBXKPZZXBBZMJF-UHFFFAOYSA-N tert-butyl 4-[[3-[3-fluoro-4-(2-methoxyethylsulfanyl)phenyl]-1,2,4-oxadiazol-5-yl]methoxy]piperidine-1-carboxylate Chemical compound C1=C(F)C(SCCOC)=CC=C1C1=NOC(COC2CCN(CC2)C(=O)OC(C)(C)C)=N1 YBXKPZZXBBZMJF-UHFFFAOYSA-N 0.000 description 1
- ZBSVPFIDGMJAKG-UHFFFAOYSA-N tert-butyl 4-[[3-[3-fluoro-4-(propanoylamino)phenyl]-1,2,4-oxadiazol-5-yl]methoxy]piperidine-1-carboxylate Chemical compound C1=C(F)C(NC(=O)CC)=CC=C1C1=NOC(COC2CCN(CC2)C(=O)OC(C)(C)C)=N1 ZBSVPFIDGMJAKG-UHFFFAOYSA-N 0.000 description 1
- ATWLZUISWKFSNL-UHFFFAOYSA-N tert-butyl 4-[[5-(4-methoxycarbonylphenyl)-1,2,4-oxadiazol-3-yl]methoxy]piperidine-1-carboxylate Chemical compound C1=CC(C(=O)OC)=CC=C1C1=NC(COC2CCN(CC2)C(=O)OC(C)(C)C)=NO1 ATWLZUISWKFSNL-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- CPIRTCVNDVQQLE-UHFFFAOYSA-N tert-butyl n-(4-cyanophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(C#N)C=C1 CPIRTCVNDVQQLE-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 1
- NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- AMIGYDGSJCJWSD-UHFFFAOYSA-N thiocane Chemical compound C1CCCSCCC1 AMIGYDGSJCJWSD-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- 230000000929 thyromimetic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000026533 urinary bladder disease Diseases 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Description
本発明は、式(I):
[式中、
Vは、O、NおよびSから選択されるヘテロ原子を4つまで含む5員ヘテロアリール環であり、それはC1-4アルキルで適宜置換され;
Aは−CH=CH−または(CH2)nであり;
Bは−CH=CH−または(CH2)nであり、その中でCH2基の1つは、O、NR5、S(O)m、C(O)、C(O)NR5、CH(NR5R55)、CH(OH)、C(O)O、C(O)S、SC(O)またはOC(O)で置き換わっていてもよく;
nは独立して、0、1、2または3であり;
mは独立して、0、1または2であり;
xは0、1、2または3であり;
yは1、2、3、4または5であるが;
但し、x+yは2、3、4または5であり;
GはCHR12またはNR2であり;
R1は、フェニル、またはO、NおよびSから選択されるヘテロ原子を4つまで含む5または6員ヘテロアリール基であり、それらのいずれもハロ、C1-4アルキル、C1-4フルオロアルキル、C1-4ヒドロキシアルキル、C2-4アルケニル、C2-4アルキニル、C3-7シクロアルキル、アリール、OR6、CN、NO2、−(CH2)j−S(O)mR6、−(CH2)j−C(O)NR6R66、NR6R66、NR10C(O)R6、NR10C(O)NR6R66、NR10SO2R6、SO2NR6R66、C(O)R10、C(O)OR10、−(CH2)j−(4〜7員ヘテロサイクリル)または−(CH2)j−(5〜6員ヘテロアリール)から選択される1つまたはそれ以上の置換基で適宜置換されていてもよいが;但し、R1は適宜置換された3−または4−ピリジル、4−または5−ピリミジニルまたは2−ピラジニルではなく;
jは0、1または2であり;
R2は、C(O)OR3、C(O)NR3R13、C1-4アルキレン−C(O)OR3、C(O)C(O)OR3、S(O)2R3、C(O)R3またはP(O)(O−Ph)2であるか;あるいはヘテロサイクリルまたはヘテロアリールであり、それらのいずれかは、C1-4アルキル、C1-4アルコキシまたはハロゲンから選択される1つまたは2つの基で適宜置換されていてもよく;
R3は、C1-8アルキル、C2-8アルケニルまたはC2-8アルキニルであり、それらのいずれも、1つまたはそれ以上のハロ原子、NR4R44、OR4、C(O)OR4、OC(O)R4またはシアノで適宜置換されていてもよく、OまたはSで置き換わるCH2基を含んでいてもよく;あるいは、C3-7シクロアルキル、アリール、ヘテロサイクリル、ヘテロアリール、C1-4アルキレンC3-7シクロアルキル、C1-4アルキレンアリール、C1-4アルキレンヘテロサイクリルまたはC1-4アルキレンヘテロアリールであり、それらのいずれも、ハロ、C1-4アルキル、C1-4フルオロアルキル、OR4、CN、NR4R44、SO2Me、NO2またはC(O)OR4から選択される1つまたはそれ以上の置換基で置換されていてもよく;
R4およびR44は独立して、水素またはC1-4アルキルであるか;あるいは、一緒になってR4およびR44は5または6員ヘテロ環を形成してもよく;
R5およびR55は独立して、水素またはC1-4アルキルを表し;
R6およびR66は独立して、水素またはC1-4アルキルであり、それはハロ、ヒドロキシ、C1-4アルキルオキシ−、C1-4アルキルチオ−、C3-7ヘテロサイクリル、−C(O)OR14またはN(R10)2で適宜置換されていてもよく;あるいは、C3-7シクロアルキル、アリール、ヘテロサイクリルまたはヘテロアリールであり、その中で環状基は、ハロ、C1-4アルキル、C1-4フルオロアルキル、OR9、CN、SO2CH3、N(R10)2およびNO2から選択される1またはそれ以上の置換基で置換されていてもよく;あるいは、一緒になってR6およびR66は、ヒドロキシ、C1-4アルキルまたはC1-4ヒドロキシアルキルで適宜置換され、OおよびNR10から選択されるヘテロ原子を更に適宜含む4〜6員ヘテロ環を形成してもよく、あるいは、R66はC1-4アルキルオキシ−であり;
R9は、水素、C1-2アルキルまたはC1-2フルオロアルキルであり;
R10は独立して、水素またはC1-4アルキルであり;あるいは、N(R10)2基は、OおよびNR10から選択されるヘテロ原子を更に適宜含む4〜7員ヘテロ環を形成してもよく;
R12はC3-6アルキルであり;
R13およびR14は独立して、水素またはC1-4アルキルである]
の化合物、またはその医薬的に許容される塩に関する。
の5員ヘテロアリール環である。
好ましくは、W、XおよびYの2つはNであり、残りはOである。
Wは好ましくはNである。
好ましくは、化学基AおよびBは両方が結合を表さない、すなわちnが各々0でない。
Aは好ましくは、(CH2)n(式中、nは好ましくは0、1または2であり、より好ましくは0である)である。
好ましくは、Bは−CH=CH−または(CH2)n(式中、CH2基の一つは、O、NR5、S(O)m、C(O)、C(O)NR5、CH(NR5R55)、C(O)O、C(O)S、SC(O)またはOC(O)で置き換わってもよい)である。
Bは好ましくは、(CH2)n(式中、nは好ましくは1、2または3でり、より好ましくは2または3、特に2が好ましい)である。
R1への好ましい置換基は、ハロ、C1-4アルキル、C1-4フルオロアルキル、C2-4アルケニル、C2-4アルキニル、CN、S(O)mR6、NR10C(O)NR6R66、C(O)NR6R66、SO2NR6R66、NR10SO2R6、COR10、C(O)OR10、または5または6員ヘテロアリール基であり;特にハロ(例えば、フルオロまたはクロロ)、C1-4アルキル、C1-4フルオロアルキル、C2-4アルケニル、C2-4アルキニル、CN、S(O)mR6、NR10C(O)NR6R66、C(O)NR6R66もしくはSO2NR6R66または5員ヘテロアリール基が好ましく;その中で特に、フルオロ、クロロ、メチル、S(O)mR6(例えば、式中、mは1または2)、NR10C(O)NR6R66、C(O)NR6R66もしくはSO2NR6R66または5員ヘテロアリール基が好ましい。
Gは好ましくはNR2である。
好ましくは、R5は水素またはメチルを表し、特にメチルが好ましい。
好ましくは、R6およびR66は独立して、水素またはC1-4アルキルであり、それはハロ(例えば、フルオロ)、ヒドロキシ、C1-4アルキルオキシ−、C1-4アルキルチオ−、C3-7ヘテロサイクリルまたはN(R10)2で適宜置換されていてもよく;あるいは、C3-7シクロアルキル、アリール、ヘテロサイクリルまたはヘテロアリールであり、その中で環状基はハロ、C1-4アルキル、C1-4フルオロアルキル、OR9、CN、SO2CH3、N(R10)2およびNO2から選択される1つまたはそれ以上の置換基で置換されてもよく;あるいは、一緒になってR6およびR66は、ヒドロキシ、C1-4アルキルまたはC1-4ヒドロキシアルキルで適宜置換された5または6員ヘテロ環を形成してもよく;あるいは、R66はC1-4アルキルオキシ−である。
好ましくは、R10は水素、メチルまたはtert−ブチルである。
好ましくは、R12はペンチルである。
好ましくは、R14は水素またはメチルである。
R13およびR15は好ましくは、独立して水素またはメチルである。
mは好ましくは、1または2である。
[式中、
Bは、(CH2)n(nは2または3)であり、CH2基の1つはOまたはNR5で置き換わっていてもよく;
R1、V、R3およびR5は、式(I)の化合物で先に記載されたものと同義である]
である。
式(Ia)の化合物の群は、式(Ib):
[式中、
RaおよびRcは独立して、水素、フッ素、塩素、メチルまたはCNを表し;
Rbは、S(O)mR6、C(O)NR6R66、SO2NR6R66、NR10C(O)R6、NR10SO2R6、NR10C(O)NR6R66または5員ヘテロアリールを表し;
R3は、メチルで適宜置換されていてもよいC2-5アルキルまたはC3-5シクロアルキルを表し;
mは1または2を表し;
R6およびR66は独立して、水素、またはヒドロキシルもしくはNH2で適宜置換されていてもよいC1-4アルキルを表すか、あるいはR6およびR66が一緒になって、OHまたはCH2OHで適宜置換された5または6員ヘテロ環を形成してもよく;および
R10は独立して、水素またはC1-4アルキルであり;あるいは、N(R10)2基は、OおよびNR10から選択されるヘテロ原子を更に適宜含む4〜7員ヘテロ環を形成してもよい]
の化合物である。
式(Ib)の化合物において、好ましくはRbは、S(O)mR6、C(O)NR6R66、NR10C(O)NR6R66、5員ヘテロアリールまたはSO2NR6R66を表す。あるいは、式(Ib)の化合物において、RbはNR10C(O)R6またはNR10SO2R6を表す。
言及されてもよい本発明の特定の化合物は、実施例に含まれる化合物およびその医薬的に許容される塩である。
i)R1がフルオロフェニルまたはジフルオロフェニルを表す場合、AおよびBは結合を表し、xは1を表し、yは3を表し、好ましくは、GはNC(O)O−フルオロフェニルを表さない。
ii)GがCHR12を表し、R12がペンチルである場合、、xは2を表し、yは2を表し、Aは結合を表し、Vは1,3,4−オキサジアゾールを表し、好ましくは、R1は3−ジメチルアミノ−ピロリジン−1−イルで置換されたフェニルを表さない。
iii)R1がフェニルを表す場合、Aは−CH2−を表し、Bは結合を表し、xは0を表し、yは4を表し、GはNR2を表し、好ましくは、R2はS(O)2R3を表さない。
iv)R1が置換フランを表す場合、AおよびBは結合を表し、xは0を表し、yは4を表し、GはNR2を表し、好ましくは、R2はS(O)2−CH2−シクロヘキシルを表さない。
v)R1が4−メタンスルホニルフェニルを表す場合、Aは結合を表し、Bは−CH2CH2−を表し、xは2を表し、yは2を表し、好ましくは、GはN−シクロプロピルを表さない。
vi)xが0を表す場合、yは3を表し、Bは結合を表し、好ましくはGはNC(O)R3を表さない。
用語「ハロ」には、フッ素、塩素、臭素、およびヨウ素原子(特に、フッ素または塩素)が含まれる。
反応式1
反応式2
反応式3
反応式4
反応式5
反応式6
反応式7
反応式8
反応式9
反応式10
反応式11
反応式12
(式中、基R1、A、V、B、xおよびyは、式(I)の化合物の場合と同義である)またはその塩もしくはその保護された誘導体である。式(XXVII)の化合物においては、R1はビフェニルを表し、AおよびBは結合を表し、xは2を表し、好ましくはyは2を表さない。
上記で述べたように式(I)の化合物は、GPR119アゴニストとして、例えば、肥満症および糖尿病の治療および/または予防に有用である。そのような用途のために、式(I)の化合物は、医薬組成物の形態で一般的に投与される。
本発明はまた、医薬用途のために、式(I)の化合物またはその医薬的に許容される塩も提供する。
本発明はまた、医薬的に許容される担体と組み合わせて、式(I)の化合物を含む医薬組成物を提供する。
好ましくは、該組成物は、医薬的に許容される担体、および式(I)の化合物またはその医薬的に許容される塩の無毒性の治療上の有効量からなる。
用いられる医薬担体は、例えば、固体、液体、または気体があり得る。固体担体の例には、乳糖、白土(terra alba)、ショ糖、タルク、ゼラチン、カンテン、パクチン、アラビアガム、ステアリン酸マグネシウム、およびステアリン酸が含まれる。液体担体の例は、糖シロップ、落花生油、オリーブ油、および水である。気体担体の例には、二酸化炭素および窒素が含まれる。
すべての場合において、最終的な注射用製剤は無菌でなければならず、容易に注入操作ができる効果的な流動性を有さなければならない。医薬組成物は製造および保存条件下安定でなければならず;したがって、好ましくは細菌および真菌のような微生物の汚染の作用に対して保護されるべきである。担体は、例えば、水、エタノール、ポリオール(例えば、グリセロール、プロピレングリコールおよび液体ポリエチレングリコール)、植物油、およびそれらの好ましい混合物を含む溶媒または分散溶媒であり得る。
本発明はまた、有効量の式(I)の化合物またはその医薬的に許容される塩を、治療が必要な患者に投与するステップを含む、満腹の制御方法も提供する。
本発明はまた、有効量の式(I)の化合物またはその医薬的に許容される塩を、治療が必要な患者に投与するステップを含む、1型および2型糖尿病(特に、2型糖尿病)を含む糖尿病の治療方法も提供する。
本発明はまた、上記で定義された症状の治療剤の製造における、式(I)の化合物またはその医薬的に許容される塩の使用も提供する。
式(I)の化合物、またはその医薬的に許容される塩は、単独で投与してもよく、または1またはそれ以上の他の治療上の活性化合物と共に投与してもよい。他の治療上の活性化合物は、式(I)の化合物の場合と同じ疾患もしくは症状、または異なる疾患もしくは症状の治療のためであってもよい。治療活性化合物は、同時、連続して、または分離して投与してもよい。
本発明はまた、肥満症治療用の別の抗肥満薬と組み合わせた薬物の製造における、式(I)の化合物またはその医薬的に許容される塩の使用を提供する。
共投与には、式(I)の化合物またはその医薬的に許容される塩、および別の抗肥満薬の両方を含んだ製剤の投与、または各剤の異なる製剤の同時もしくは別々の投与が含まれる。式(I)の化合物またはその医薬的に許容される塩、および他の抗肥満薬のプロファイルが許容するなら、その2つの薬剤の組合せが好ましい場合がある。
GPR119アゴニストは、中枢性抗肥満薬と組み合わせた特異的な使用である。
本発明は、詳述する目的で以下の例に関して記載するが、本発明の範囲を限定する趣旨ではない。
略語
Boc:tert−ブトキシカルボニル;
t−Bu:tert−ブチル;
DCM:ジクロロメタン;
DMAP:4−ジメチルアミノピリジン;
DMF:N,N−ジメチルホルムアミド;
h:時間;
DMSO:ジメチルスルホキシド;
EDC:1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸;
EtOAc:酢酸エチル;
HOBt:1−ヒドロキシベンゾトリアゾール水和物;
HPLC:高速液体クロマトグラフィー;
mCPBA:3−クロロペルオキシ安息香酸;
IH:イソヘキサン;
Me:メチル;
min:分;
RP−HPLC:
逆相高速液体クロマトグラフィー;
rt:室温;
RT:保持時間;
TFA:トリフルオロ酢酸;
THF:テトラヒドロフラン。
以下のようにLCMSデータを得た:
Waters Xterra MS C18,5μM(4.6×50mm、流速1.5mL/分)を用い、215および254nmでのUV検出で、0.1容積% アンモニアを含有するH2O−MeCN グラジエントで12分かけて溶離する。
グラジエント情報:
0.0〜8.0分:95% H2O−5% MeCNから5% H2O−95% MeCNへの勾配;
8.0〜9.9分:5% H2O−95% MeCNで保持;
9.9〜10.0分:95% H2O−5% MeCNに戻す;
10.0〜12.0分:95% H2O−5% MeCNで保持。
陽イオン(ESI+)または陰イオン(ESI-)モードにおいて、エレクトロスプレーイオン化イオン源(electrospray ionization source)を用いて、質量スペクトルを得た。
以下のようにLCMSデータを得た:
Waters Atlantis C18,3μ(3.0×20mm、流速0.85mL/分)を用い、220nmでのUV検出で、0.1容積% HCO2Hを含有するH2O−MeCN グラジエントで6.5分かけて溶離する。
グラジエント情報:
0.0〜0.3分 100% H2O;
0.3〜4.25分:10% H2O−90% CH3CNへの勾配;
4.25〜4.4分:100% CH3CNへの勾配;
4.4〜4.9分:100% MeCNで保持;
4.9〜5.0分:100% H2Oに戻す;
5.00〜6.50分:100% H2Oで保持。
陽イオン(ESI+)または陰イオン(ESI-)モードにおいて、エレクトロスプレーイオン化イオン源を用いて、質量スペクトルを得た。1H NMRスペクトルを、バリアン マーキュリー(Varian Mercury)400分光計において、400MHzで操作して記録した。化学シフトを、テトラメチルシラン(δ=0)に対するppmとして記録する。
0〜0.5分、10% CH3CN−90% H2O;
0.5〜10分、90% CH3CN−10% H2Oへの勾配、および90% CH3CN−10% H2Oで5分間保持;
15〜16分、10% CH3CN−90% H2Oに戻す。
3−ヒドロキシメチルアゼチジン−1−カルボン酸tert−ブチルエステル:Slusarchyk S. A.ら, Bioorg. Med. Chem. Lett., 2002, 12, 3235-3238;(4−シアノフェニル)カルバミン酸 tert−ブチルエステル:Sendzik M.ら, Tetrahedron Lett. 2003, 44, 8697-8700。
攪拌したこのアルデヒド(1.0g、5.32mmol)のEtOH溶液(12mL)を、まずNH2OH.HCl(778mg、11.2mmol)の水溶液(5mL)で処理し、続いてK2CO3(780mg、5.64mmol)の水溶液(10mL)で処理した。1時間後、EtOHを減圧留去し、残存する水層をEtOAc(100mL)で抽出した。有機層を乾燥し(MgSO4)、蒸発させ、残留物をカラムクロマトグラフィー(IH−EtOAc 9:1)によって精製して、3,5−ジフルオロ−4−メチルスルファニルベンズアルデヒドオキシムを得た:δH(CDCl3) 2.50 (3H, s), 7.14 (2H, d), 7.47 (1H, s)および8.03 (1H, s).
このオキシムのサンプル(1.14g、5.6mmol)、p−トルエンスルホン酸(1.07g、5.6mmol)および無水酢酸(45mL)を、還流下で20時間加熱した。冷却しながら、溶媒を蒸発させ、Na2CO3水溶液(10mL)を加え、水層がpH 8であることを確認した。混合物をDCM(2×100mL)で抽出し、有機層を合わせて乾燥し(MgSO4)、蒸発させ、残留物をカラムクロマトグラフィー(IH−EtOAc 9:1)によって精製して、標題のニトリルを得た:δH(CDCl3) 2.58 (3H, s), 7.20 (2H, d).
アンモニアガスを、塩化スルホニル(80mg、365μmol)の攪拌した溶液を通して10分間バブリングした。次いで溶媒を除去し、カラムクロマトグラフィー(IH−EtOAc 2:1)によって残留物を精製して、標題のニトリルを得た:δH(d6-DMSO) 7.88 (1H, dd), 7.95 (2H, br s) 7.96 (1H, t), 8.11 (1H, dd).
製造20で概説した方法を用いて、チオレートの、適当な4−フルオロベンゾニトリルとの反応によって、表1に列挙した化合物を製造した。
アルコールのこの混合物のサンプル(277mg、1.03mmol)をDCM(5mL)に溶解し、塩化チオニル(600μl、8.22mmol)を加えた。17時間攪拌後、溶媒を除去し、カラムクロマトグラフィー(IH−EtOAc 1:1)によって残留物を精製して、4−クロロメチル−1−(4−メタンスルホニルフェニル)−1H−[1,2,3]トリアゾールおよび5−クロロメチル−1−(4−メタンスルホニルフェニル)−1H−[1,2,3]トリアゾールの混合物を得た:RT=2.72分;m/z(ES+)=272.0[M+H]+。
塩化物(430mg、1.58mmol)、LiBr(1.41g、15.8mmol)およびアセトン(10mL)のこの混合物の溶液を、還流下で3時間加熱した。次いで溶媒を除去し、残留物をDCM(20mL)に溶解し、水(10mL)で洗浄した。有機層を疎水性のフリットに通し、蒸発させ、カラムクロマトグラフィー(IH−EtOAc 7:3)によって残留物を精製して、標題の臭化物を得た:RT 2.65分(方法2);m/z(ES+)=318.0[M+H]+。
このエステルのサンプル(810mg、2.76mmol)を無水THF溶液(10mL)に溶解し、アルゴン下で0℃まで冷却し、LiAlH4(1M THF溶液、3mL、3mmol)を加えた。1時間攪拌後、水(1mL)を含有するTHF(20mL)の添加によって反応をクエンチし、ロッシェル塩水溶液(0.5M、10mL)で希釈した。混合物をEtOAc(2×100mL)で抽出し、有機層を合わせて乾燥し(MgSO4)、蒸発させて、[1−(4−メタンスルホニルフェニル)−1H−ピラゾール−4−イル]メタノールを得た:RT=2.30分;m/z(ES+)=253.0[M+H]+。
このアルコールのサンプル(570mg、2.25mmol)およびDMF(10μl)の乾燥DCM溶液(15mL)を、塩化チオニル(370μl、5.0mmol)で処理した。17時間攪拌後、溶媒を除去し、カラムクロマトグラフィー(IH−EtOAc 1:1)によって残留物を精製して、4−クロロメチル−1−(4−メタンスルホニルフェニル)−1H−ピラゾールを得た:RT=3.01分;m/z(ES+)=271.0[M+H]+。
この塩化物(212mg、780μmol)およびLiBr(347mg、3.9mmol)の混合物のアセトン溶液(50mL)を、還流下で3時間加熱し、冷却し、溶媒を除去した。残留物をCH2Cl2(20mL)に溶解し、水(10mL)で洗浄し、疎水性のフリットを通すことによって有機層を乾燥した。蒸発にさせることよって、標題の臭化物を得た:RT=3.09分(方法2);m/z(ES+)=315.0[M+H]+。
攪拌したこのエステル(1.0g、5.7mmol)の無水DMF溶液(15mL)を−78℃まで冷却し、ナトリウムチオメトキシド(402mg、5.7mmol)の無水DMF懸濁液を加えた。混合物を室温まで2.5時間かけて加温し、水(25mL)に注いだ。EtOAc(150mL)の中に抽出した後、有機層を水(20mL)で洗浄し、乾燥し(MgSO4)、乾燥するまで蒸発させた。カラムクロマトグラフィー(IH−DCM 7:3)による残留物の精製によって、2,5−ジフルオロ−4−メチルスルファニル安息香酸メチルエステルを得た:δH(CDCl3) 2.50 (3H, s), 3.92 (3H, s), 6.91 (1H, dd), 7.57 (1H, dd).
このエステル(300mg、1.4mmol)のMeOH溶液(15mL)をLiOH(645mg、15mmol)で処理し、混合物を室温で2時間攪拌した。濃HClを用いてpH 1まで酸性化した後、小容量になるまでメタノールを蒸発させ、標題の酸を濾過によって回収した:δH(CDCl3) 2.48 (3H, s), 6.89 (1H, dd), 7.57 (1H, dd).
このエステルのサンプル(933mg、3.25mmol)をMeOH溶液(10mL)に溶解し、NaOH水溶液(2M 溶液、3.25mL、6.5mmol)を加えた。1時間攪拌後、溶媒を蒸発させ、残留物を水(50mL)に溶解し、エーテル(20mL)で洗浄した。希HClを用いてpH 2まで水層を酸性化し、EtOAc(100mL)の中に抽出した。有機層の乾燥(MgSO4)および溶媒の除去によって、標題の酸を得た:δH(CDCl3) 1.46 (9H, s), 1.54 (2H, m), 1.82 (2H, m), 2.64 (2H, t), 3.12 (2H, ddd), 3.51 (1H, dddd), 3.72 (2H, m), 3.75 (2H, t).
3−(4−メタンスルホニルフェニル)−[1,2,4]オキサジアゾール−5−オールのサンプル(1.23g、5.15mmol)をPOCl3(30mL)に溶解し、穏やかな還流下で加熱し、ピリジン(0.42mL、5.12mmol)および4−DMAP(4mg)を加えた。加熱を22時間続け、その上で混合物を冷却し、氷/水(300mL)の上に注いだ。水層をEtOAc(3×150mL)で抽出し、有機層を合わせて食塩水で洗浄し、乾燥し(MgSO4)、蒸発させて、標題のクロロオキサジアゾールを得た:δH(d6-DMSO) 3.30 (3H, s), 8.14 (2H, d), 8.24 (2H, d).
このチオエーテルのサンプル(1.0g、5.38mmol)を水中に懸濁し、次いでNaH2PO4(705mg、5.88mmol)、tert−ブタノール(44mL)および亜塩素酸ナトリウム(1.59g、63mmol)を加えた。1.5時間勢いよく攪拌した後、tert−ブタノールを減圧留去し、EtOAc(50mL)を加えた。混合物を1M NaOH水溶液(3×20mL)で抽出し、抽出物を合わせて、希HClを用いてpH 2まで酸性化した。沈殿物をEtOAcの中に抽出し、それを乾燥し(MgSO4)、蒸発させて、標題のスルホキシドの分離できない混合物を得た:RT=2.22分(方法2);m/z(ES+)=203.0[M+H]+、およびスルホン 2.22分(方法2);m/z(ES+)=219.0[M+H]+。
方法A:
4−[5−(3−シアノ−4−メトキシフェニル)−[1,2,4]オキサジアゾール−3−イルメトキシ]ピペリジン−1−カルボン酸tert−ブチルエステル(実施例1)
4−[5−(4−メタンスルホニルフェニル)−[1,2,4]オキサジゾール−3−イルメトキシ]ピペリジン−1−カルボン酸tert−ブチルエステル(実施例2)
4−[5−(2−フルオロ−4−メタンスルホニルフェニル)−[1,2,4]オキサジゾール−3−イルメトキシ]ピペリジン−1−カルボン酸tert−ブチルエステル(実施例3)
4−[5−(4−メタンスルファニルフェニル)−[1,2,4]オキサジゾール−3−イルメトキシ]ピペリジン−1−カルボン酸tert−ブチルエステル(実施例4)
4−[3−(4−メチルスルファニルフェニル)−[1,2,4]オキサジアゾール−5−イルメトキシ]ピペリジン−1−カルボン酸tert−ブチルエステル(実施例5)
4−[5−(3−シアノ−4−フルオロフェニル)−[1,2,4]オキサジアゾール−3−イルメトキシ]ピペリジン−1−カルボン酸tert−ブチルエステル(実施例6)
表3に列挙した各オキサジアゾールを、示した一般的な方法を用いて合成した。
無溶媒EtOAcでさらに溶離することによって、標題のスルホキシドを得た:δH(CDCl3) 1.49 (9H, s), 1.67 (2H, m), 1.94 (2H, m), 2.81 (3H, s), 3.18 (2H, m), 3.76 (1H, m), 3.82 (2H, m), 4.89 (2H, s), 7.81 (2H, d), 8.30 (2H, d).
スルフィドを1当量のmCPBAと反応させることによって、スルホキシドのみを得;2当量と反応させることによって、唯一の生成物としてスルホンを得た。
表4に列挙した化合物を、実施例96および97で概説した方法を用いてmCPBAで酸化することによって生成し、LCMS法2によって分析した。
実施例147に概説した方法に従って、適当なピペリジンを必要なクロロホルメートと反応させることによって、表5に列挙したカルバメートを合成した。
表6における化合物を、実施例163に記載したものと類似する方法で合成した。
表7
このチオエーテルのサンプルを、実施例96および97に記載した手順を用いて酸化して、標題のスルホンを得た:RT=3.67分(方法2);m/z(ES+)=500.0[M+H]+。
表8に列挙した5−アルコキシ−[1,2,4]オキサジアゾールを、実施例220に記載したものに類似する方法を用いて製造した。
表8に列挙した5−アルキルアミノ[1,2,4]オキサジアゾールを、適当なアミンの、5−クロロ−3−(4−メタンスルホニルフェニル)−[1,2,4]オキサジアゾールとの反応によって同様に製造した。
このアニリンのサンプル(110mg、281μmol)の無水THF溶液(5mL)を、まずトリエチルアミン(117μl、840μmol)で処理し、次いで塩化プロピオニル(49μl、560μmol)で処理した。17時間攪拌後、反応混合物をEtOAc(80mL)で希釈し、飽和NaHCO3水溶液(10mL)、食塩水(10mL)で洗浄し、乾燥した(MgSO4)。溶媒の除去およびカラムクロマトグラフィー(IH−EtOAc 3:2)による残留物の精製によって、標題のアミドを得た RT=3.74分(方法2);m/z(ES+)=449.1[M+H]+。
酵母レポーターアッセイ
酵母細胞に基づくレポーターアッセイは、先に文献に記載されている(例えば、Miret J. J.ら, 2002, J. Biol. Chem., 277:6881-6887;Campbell R.M.ら, 1999, Bioorg. Med. Chem. Lett., 9:2413-2418;King K.ら, 1990, Science, 250:121-123);WO 99/14344;WO 00/12704;およびUS 6,100,042を参照)。簡単に言えば、内在性酵母G−アルファ(GPA1)が欠失され、複数の技術を用いて作成されるG−タンパク質キメラで置換されているように、酵母細胞は改変されている。また、内在性酵母GPCR、Ste3は欠失されて、好んで用いられる哺乳類GPCRの異種発現を可能にしている。酵母において、真核細胞で保存される(例えば、***促進因子活性化タンパク質キナーゼ経路)フェロモンシグナル伝達経路の要素は、Fus1の発現を促進する。Fus1プロモーター(Fus1p)の制御下でβ−ガラクトシダーゼ(LacZ)を置換することによってシステムが開発されており、それによって受容体の活性化が酵素の読み取りにつながる。
組換えヒトGPR119を発現する安定な細胞株を確立し、この細胞株を用いて、環状AMP(cAMP)の細胞内濃度における本発明の化合物の効果を調査した。細胞単層をリン酸緩衝生理食塩水で洗浄し、刺激用緩衝液(stimulation buffer)における様々な濃度の化合物に1% DMSOを加えたもので、37℃で30分間刺激した。次いで細胞を溶解し、パーキンエルマー アルファスクリーン(AlphaScreen)(登録商標)(増幅ルミネッセンス近接ホモジニアスアッセイ(Amplified Luminescent Proximity Homogeneous Assay))cAMPキットを用いて、cAMP量を決定した。緩衝液およびアッセイ条件は、製造業者のプロトコルに記載されているようにした。
本発明の化合物は、細胞内cAMP濃度における濃度依存性の増加を生じ、一般に<10μMのEC50を有していた。cAMPアッセイにおいて1μM未満のEC50を示す化合物が好ましい。
体重並びに餌および水の摂取における本発明の化合物の効果を、逆相照明(reverse-phase lighting)上に維持した自由にフィードされる雄のスプラーグドーリーラットにおいて試験した。試験化合物および対照化合物を、適当な投与経路(例えば腹腔内または経口)で投与し、測定を次の24時間かけて行った。21±4℃の温度、55±20% 湿度で、金属グリッドの床を有するポリプロピレンケージの中に、ラットを個々に入れた。ケージパッドを有するポリプロピレントレイを各ケージの下において、いずれのこぼれた餌も検出した。動物を逆相明暗サイクル(09.30〜17.30の8時間は電気を消す)上に維持し、その時間、部屋を赤色光で照らした。動物は、二週間の順化期間に、標準的な粉末状のラットの餌および生水を自由に得ることができた。餌を、アルミニウム蓋を有するガラスフィード瓶(feeding jar)の中に入れた。各蓋は、その中に3〜4cmのウェルを有しており、餌を得ることができた。暗期開始時に動物、フィード瓶および採水瓶の重さ(0.1gの位まで)を量った。続いて、本発明の化合物を動物に投与した1、2、4、6および24時間後に、フィード瓶および採水瓶の重さを量り、ベヒクル処置したコントロールと比較して、ベースラインでの処置群間のいずれの有意差も測定した。
本発明の選択された化合物は、一つ以上の時点で、≦100mg/kgの用量で、統計的に有意な食欲減退効果を示した。
細胞培養
HIT−T15細胞(60継代)をATCCから入手し、10% ウシ胎児血清および30nM 亜セレン酸ナトリウムを補充したRPMI1640培地中で培養した。全ての実験を、文献に従って70継代未満での細胞で行い、その文献には、81超の継代数でこの細胞株の変化した特性が記載されている(Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes. 1989 Jan;38(1):44-8)。
HIT−T15細胞を、96ウェルプレートにおいて、100,000細胞/0.1ml/ウェルで、標準的な培地中に蒔き(プレートし)、24時間培養し、次いで培地を廃棄した。細胞を、100μl 刺激用緩衝液(ハンクス緩衝塩類溶液(Hanks buffered salt solution)、5mM ヘペス、0.5mM IBMX、0.1% BSA、pH 7.4)を用いて、室温で15分間インキュベートした。これを廃棄し、0.5% DMSOの存在下、刺激用緩衝液中、0.001、0.003、0.01、0.03、0.1、0.3、1、3、10、30μMの範囲にわたる化合物希釈液と取り替えた。細胞を室温で30分間インキュベートした。次いで1ウェルあたり75μl 溶解緩衝液(5mM ヘペス、0.3% ツイーン−20(Tween-20)、0.1% BSA、pH 7.4)を加え、プレートを900rpmで20分間振とうした。粒子状物質を遠心分離によって3000rpmで5分間除去し、次いでサンプルを384ウェルプレートに移したものを2つ作成し、パーキンエルマー アルファスクリーンcAMPアッセイキットの指示書に従って処理した。簡単に言えば、最終的な反応成分の濃度がキットの説明書に記載されたものと同じになるように、サンプル(8μl)、アクセプタービーズ混合物(acceptor bead mix)(5μl)および検出混合物(detection mix)(12μl)を含む反応物(25μl)を用意した。反応を室温で150分間インキュベートし、プレートをパッカード融合装置(Packard Fusion instrument)を用いて読み取った。cAMPについての測定を、公知のcAMP量(0.01、0.03、0.1、0.3、1、3、10、30、100、300、1000nM)の検量線と比較して、測定値を絶対cAMP量に変換した。データをXLfit 3 ソフトウェアを用いて解析した。
本発明の代表的な化合物は、10μM未満のEC50でcAMPを増大させることが分かった。cAMPアッセイにおいて1μM未満のEC50を示す化合物が好ましい。
HIT−T15細胞を、12ウェルプレートにおいて、106細胞/1ml/ウェルで、標準的な培地中に蒔き(プレートし)、3日間培養し、次いで培地を廃棄した。NaCl(119mM)、KCl(4.74mM)、CaCl2(2.54mM)、MgSO4(1.19mM)、KH2PO4(1.19mM)、NaHCO3(25mM)、pH 7.4でのヘペス(10mM)および0.1% ウシ血清アルブミンを含有する補充したクレブス・リンガー緩衝液(KRB)で、細胞を洗浄した(×2)。細胞を、37℃で30分間、KRB(1ml)でインキュベートし、次いでそれを廃棄した。これに続いて30分間、KRBで第2のインキュベーションを行い、それを回収し、各ウェルの基礎インスリン分泌量を測定するために用いた。次いで化合物の希釈液(0、0.1、0.3、1、3、10μM)を、グルコース(5.6mM)で補充したKRB(1ml)に加えて、ウェルを2つ作成した。37℃で30分のインキュベーション後、インスリン量の決定のため、サンプルを取り除いた。メルコディア(Mercodia) ラット インスリン ELISAキットを用い、製造者の指示書に従って、公知のインスリン濃度の検量線を用いてインスリンの測定を行った。各ウェルについて、グルコース不存在下でプレインキュベーションから基礎分泌量を差し引くことによって、インスリン量を補正した。データをXLfit 3 ソフトウェアを用いて解析した。
本発明の代表的な化合物は、10μM未満のEC50でインスリン分泌を増大させることが分かった。インスリン分泌アッセイにおいて1μM未満のEC50を示す化合物が好ましい。
経口グルコース(Glc)耐性についての本発明の化合物の効果を、雄のC57Bl/6または雄のob/obマウスにおいて評価した。Glcの投与の5時間前に餌を取り出し、本研究の間、取り出したままにした。マウスは本研究の間、自由に水を得ることができた。Glc負荷の投与の45分前に基礎Glc量を測定するために、動物の尾に切れ目を入れ、次いで血液(20μL)を除去した。次いで、マウスの重さを量り、試験化合物またはベヒクル(20% ヒドロキシプロピル−β−シクロデキストリン水溶液または25%ゲルーシア(Gelucire) 44/14水溶液)を経口投与し、30分後に別の血液サンプル(20μL)を除去し、Glc負荷(2〜5g kg-1 経口)で処置した。次いで血液サンプル(20μL)を、Glc投与の25、50、80、120、および180分後に採った。Glc量の測定用血液サンプル(20μL)を、尾の切れ目の先(cut tip)から使い捨てのマイクロピペット(デイド・ダイアグノスティクス社(Dade Diagnostics Inc.)、プエルトリコ)の中に取り、サンプルを溶血試薬(480μL)に加えた。次いで希釈して溶血した血液アリコート(20μL)の一対を、96ウェルアッセイプレートにおいてトリンダーズ グルコース試薬(Trinders glucose reagent)(シグマ 酵素(トリンダー(Trinder))比色法)(180μL)に加えた。混合した後、サンプルを室温で30分間放置し、次いでGlcスタンダード(シグマ グルコース/尿素 窒素 複合標準セット(glucose/urea nitrogen combined standard set))に対して読み取った。本発明の代表的な化合物によって、≦100mg kg-1の用量で、Glcエクスカーション(Glc excursion)が統計的に減少した。
Claims (9)
- 式(Ib):
[式中、
Vは、トリアゾール、オキサジアゾール、およびピラゾールから選択され、それはC1−4アルキルで適宜置換され;
Bは−CH=CH−または(CH2)nであり、その中でCH2基の1つは、O、NR5、S(O)m、C(O)、C(O)NR5、CH(NR5R55)、CH(OH)、C(O)O、C(O)S、SC(O)またはOC(O)で置き換わっていてもよく;
nは独立して、0、1、2または3であり;
RaおよびRcは独立して、水素、フッ素、塩素、メチルまたはCNを表し;
Rbは、S(O)mR6、C(O)NR6R66、SO2NR6R66、NR10C(O)R6、NR10SO2R6、NR10C(O)NR6R66または5員ヘテロアリールを表し;
R3は、メチルで適宜置換されていてもよいC2−5アルキルまたはC3−5シクロアルキルを表し;
mは1または2を表し;
R5およびR55は独立して、水素またはC1−4アルキルを表し;
R6およびR66は独立して、水素、またはヒドロキシルもしくはNH2で適宜置換されていてもよいC1−4アルキルを表すか、あるいはR6およびR66が一緒になって、OHまたはCH2OHで適宜置換された5または6員ヘテロ環を形成してもよく;および
R10は独立して、水素またはC1−4アルキルであり;あるいは、N(R10)2基は、OおよびNR10から選択されるヘテロ原子を更に適宜含む4〜7員ヘテロ環を形成してもよい]
の化合物、またはその医薬的に許容される塩。 - Vがオキサジアゾールである、請求項1の化合物、またはその医薬的に許容される塩。
- Bが(CH2)n(nは1、2または3)である、請求項1または2の化合物、またはその医薬的に許容される塩。
- B中nが2または3である、請求項3の化合物、またはその医薬的に許容される塩。
- B中nが2である、請求項4の化合物、またはその医薬的に許容される塩。
- 薬物として使用するための請求項1〜6のいずれか一つの化合物またはその医薬的に許容される塩。
- 満腹の調節、あるいは肥満症、糖尿病、メタボリックシンドローム(シンドロームX)、耐糖機能障害、高脂血症、高トリグリセリド血症、高コレステロール血症、低HDLレベル症または高血圧症の治療または予防のために薬物の製造に用いるための、請求項1〜6のいずれか一つの化合物またはその医薬的に許容される塩。
- 満腹の調節、あるいは肥満症、糖尿病、メタボリックシンドローム(シンドロームX)、耐糖機能障害、高脂血症、高トリグリセリド血症、高コレステロール血症、低HDLレベル症または高血圧症の治療または予防に使用するための、請求項1〜6のいずれか一つの化合物またはその医薬的に許容される塩。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0513257.6 | 2005-06-30 | ||
GB0513257A GB0513257D0 (en) | 2005-06-30 | 2005-06-30 | Compounds |
GB0605539A GB0605539D0 (en) | 2006-03-20 | 2006-03-20 | Compounds |
GB0605539.6 | 2006-03-20 | ||
PCT/GB2006/050176 WO2007003960A1 (en) | 2005-06-30 | 2006-06-29 | Gpcr agonists |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2008545007A JP2008545007A (ja) | 2008-12-11 |
JP5114395B2 true JP5114395B2 (ja) | 2013-01-09 |
Family
ID=37604118
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008520006A Expired - Fee Related JP5114395B2 (ja) | 2005-06-30 | 2006-06-29 | Gpcrアゴニスト |
Country Status (4)
Country | Link |
---|---|
US (1) | US20090325924A1 (ja) |
EP (1) | EP1907383A1 (ja) |
JP (1) | JP5114395B2 (ja) |
WO (1) | WO2007003960A1 (ja) |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DOP2006000008A (es) * | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1 |
BRPI0710839A2 (pt) * | 2006-04-06 | 2011-08-23 | Prosidion Ltd | agonistas heterocìclicos de gpcr |
PE20071221A1 (es) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas |
CL2007001011A1 (es) | 2006-04-11 | 2008-05-16 | Arena Pharm Inc | Metodo para la identificacion de secretagogos de gip, polipeptido inhibidor gastrico; y uso de un receptor acoplado a proteina g para clasificar compuestos de prueba como secretagogos de gip. |
GB0610746D0 (en) * | 2006-06-01 | 2006-07-12 | Prosidion Ltd | Method of treatment |
AU2007283113A1 (en) | 2006-08-08 | 2008-02-14 | Sanofi-Aventis | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use |
AU2007334436A1 (en) | 2006-12-15 | 2008-06-26 | Abbott Laboratories | Novel oxadiazole compounds |
US7638541B2 (en) | 2006-12-28 | 2009-12-29 | Metabolex Inc. | 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine |
ATE523507T1 (de) | 2007-01-04 | 2011-09-15 | Prosidion Ltd | Piperidin-gpcr-agonisten |
EA016507B1 (ru) | 2007-01-04 | 2012-05-30 | Прозидион Лимитед | Пиперидиновые агонисты gpcr |
PE20081659A1 (es) | 2007-01-04 | 2008-10-24 | Prosidion Ltd | Agonistas de gpcr |
GB0700122D0 (en) | 2007-01-04 | 2007-02-14 | Prosidion Ltd | GPCR agonists |
AR064736A1 (es) | 2007-01-04 | 2009-04-22 | Prosidion Ltd | Agonistas de gpcr |
ATE482209T1 (de) * | 2007-03-08 | 2010-10-15 | Irm Llc | Verbindungen und zusammensetzungen als modulatoren der gpr119-aktivität |
UA99284C2 (ru) | 2007-05-11 | 2012-08-10 | Елі Ліллі Енд Компані | ИНГИБИТОРЫ р70 S6-КИНАЗЫ |
PE20090449A1 (es) * | 2007-07-17 | 2009-04-18 | Bristol Myers Squibb Co | Agonistas de receptor acoplado a proteina g gpr119 de piridona |
KR20100033419A (ko) | 2007-07-19 | 2010-03-29 | 메타볼렉스, 인코포레이티드 | 당뇨병 및 대사 장애의 치료를 위한 rup3 또는 gpr119 수용체의 작용제로서 n-아자시클릭 치환된 피롤, 피라졸, 이미다졸, 트리아졸 및 테트라졸 유도체 |
EP2025674A1 (de) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
WO2009029632A1 (en) * | 2007-08-27 | 2009-03-05 | Helicon Therapeutics, Inc. | Therapeutic isoxazole compounds |
EP2200609A1 (en) | 2007-09-10 | 2010-06-30 | Prosidion Limited | Compounds for the treatment of metabolic disorders |
BRPI0817211A2 (pt) | 2007-09-20 | 2017-05-16 | Irm Llc | composto composições como moduladores da atividade de gpr119 |
GB0720389D0 (en) | 2007-10-18 | 2008-11-12 | Prosidion Ltd | G-Protein Coupled Receptor Agonists |
GB0720390D0 (en) | 2007-10-18 | 2007-11-28 | Prosidion Ltd | G-Protein coupled receptor agonists |
BRPI0909469A2 (pt) * | 2008-03-31 | 2015-12-29 | Metabolex Inc | compostos de oximetileno de arila e usos dos mesmos |
EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
UY31968A (es) | 2008-07-09 | 2010-01-29 | Sanofi Aventis | Nuevos derivados heterocíclicos, sus procesos para su preparación, y sus usos terapéuticos |
CA2730511C (en) * | 2008-07-11 | 2013-06-11 | Robert Epple | 4-phenoxymethylpiperidines as modulators of gpr119 activity |
WO2010013849A1 (ja) | 2008-08-01 | 2010-02-04 | 日本ケミファ株式会社 | Gpr119作動薬 |
AR074072A1 (es) | 2008-11-11 | 2010-12-22 | Lilly Co Eli | Compuesto de imidazol -piperidin -pirrol-pirimidin-6-ona, composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para tratar el glioblastoma multiforme |
EP2379542B1 (en) * | 2008-12-24 | 2013-02-13 | Cadila Healthcare Limited | Novel oxime derivatives |
GB0904287D0 (en) | 2009-03-12 | 2009-04-22 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
GB0904285D0 (en) | 2009-03-12 | 2009-04-22 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
GB0904284D0 (en) | 2009-03-12 | 2009-04-22 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
AU2010264720A1 (en) | 2009-06-24 | 2011-12-08 | Boehringer Ingelheim International Gmbh | New compounds, pharmaceutical composition and methods relating thereto |
WO2010149685A1 (en) | 2009-06-24 | 2010-12-29 | Boehringer Ingelheim International Gmbh | New compounds, pharmaceutical composition and methods relating thereto |
JP2012180281A (ja) * | 2009-06-29 | 2012-09-20 | Dainippon Sumitomo Pharma Co Ltd | 新規オキサジアゾール誘導体 |
AU2010279964B2 (en) | 2009-08-05 | 2016-02-11 | Daiichi Sankyo Company, Limited | Amide derivative |
JP5546543B2 (ja) | 2009-08-05 | 2014-07-09 | 第一三共株式会社 | スルホン誘導体 |
EP2474540A4 (en) | 2009-08-31 | 2013-03-13 | Nippon Chemiphar Co | GPR119 AGONIST |
US8410127B2 (en) | 2009-10-01 | 2013-04-02 | Metabolex, Inc. | Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts |
US20130109703A1 (en) | 2010-03-18 | 2013-05-02 | Boehringer Ingelheim International Gmbh | Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions |
GB201006166D0 (en) | 2010-04-14 | 2010-05-26 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
GB201006167D0 (en) | 2010-04-14 | 2010-05-26 | Prosidion Ltd | Compounds for the treatment of metabolic disorders |
MX2012012902A (es) * | 2010-05-06 | 2012-12-17 | Bristol Myers Squibb Co | Analogos heteroarilo biciclicos como moduladores de receptor acoplado a la proteina g gpr119. |
TW201209054A (en) | 2010-05-28 | 2012-03-01 | Prosidion Ltd | Novel compounds |
EP2582709B1 (de) | 2010-06-18 | 2018-01-24 | Sanofi | Azolopyridin-3-on-derivate als inhibitoren von lipasen und phospholipasen |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
CN103037843A (zh) | 2010-06-23 | 2013-04-10 | 麦它波莱克斯股份有限公司 | 5-乙基-2-{4-[4-(4-四唑-1-基-苯氧甲基)-噻唑-2-基]-哌啶-1-基}-嘧啶的组合物 |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
SI2628733T1 (sl) | 2010-10-14 | 2015-10-30 | Daiichi Sankyo Company, Limited | Derivati acilbenzena |
AR083904A1 (es) | 2010-11-18 | 2013-04-10 | Prosidion Ltd | Derivados de 1,4-pirrolidinas disustituidos y 3-il-aminas y sus usos en el tratamiento de desordenes metabolicos |
GB201114389D0 (en) | 2011-08-22 | 2011-10-05 | Prosidion Ltd | Novel compounds |
JP2014094886A (ja) * | 2011-02-28 | 2014-05-22 | Nippon Chemiphar Co Ltd | Gpr119作動薬 |
WO2012120052A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8828994B2 (en) | 2011-03-08 | 2014-09-09 | Sanofi | Di- and tri-substituted oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof |
EP2683699B1 (de) | 2011-03-08 | 2015-06-24 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120053A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
WO2012145604A1 (en) * | 2011-04-22 | 2012-10-26 | Arena Pharmaceuticals, Inc. | Modulators of the gpr119 receptor and the treatment of disorders related thereto |
US8895587B2 (en) | 2011-05-18 | 2014-11-25 | Syngenta Participations Ag | Insecticidal compounds based on arylthioacetamide derivatives |
AU2012267556B9 (en) | 2011-06-09 | 2017-05-11 | Rhizen Pharmaceuticals Sa | Novel compounds as modulators of GPR-119 |
JP5973440B2 (ja) | 2011-07-29 | 2016-08-23 | 第一三共株式会社 | N−ヘテロ環置換アミド誘導体 |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
MX2014008790A (es) | 2012-01-18 | 2014-10-13 | Daiichi Sankyo Co Ltd | Derivado de fenilazol sustituido. |
US20140057926A1 (en) | 2012-08-23 | 2014-02-27 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
US20140057920A1 (en) | 2012-08-23 | 2014-02-27 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
CA3032432A1 (en) | 2016-08-03 | 2018-02-08 | Charles A. Mcwherter | Oxymethylene aryl compounds for treating inflammatory gastrointestinal diseases or gastrointestinal conditions |
EP3642187A1 (en) * | 2017-06-19 | 2020-04-29 | Basf Se | 2-[[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]aryloxy](thio)acetamides for combating phytopathogenic fungi |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3092637A (en) * | 1961-02-27 | 1963-06-04 | Du Pont | Process for the preparation of acetals and ketals of nu, nu-disubstituted carboxamides |
US5622976A (en) * | 1991-12-31 | 1997-04-22 | Fujisawa Pharmaceutical Co., Ltd. | Oxadiazole derivatives having acetylcholinesterase-inhibitory and muscarinic agonist activity |
WO1995032965A1 (fr) * | 1994-06-01 | 1995-12-07 | Yamanouchi Pharmaceutical Co. Ltd. | Derive de l'oxadiazole et composition medicinale a base de ce dernier |
FR2728901B1 (fr) * | 1994-12-28 | 1997-03-28 | Sanofi Sa | Derives de phenyl-4-thiazoles substitues, procede pour leur preparation et compositions pharmaceutiques les contenant |
DE19620041A1 (de) * | 1996-05-17 | 1998-01-29 | Merck Patent Gmbh | Adhäsionsrezeptor-Antagonisten |
WO1997046556A1 (en) * | 1996-06-07 | 1997-12-11 | Merck & Co., Inc. | OXADIAZOLE BENZENESULFONAMIDES AS SELECTIVE β3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY |
DE19858193A1 (de) * | 1998-12-17 | 2000-06-21 | Aventis Cropscience Gmbh | 4-Trifluormethyl-3-oxadiazolylpyridine, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung als Schädlingsbekämpfungsmittel |
JP2000093749A (ja) * | 1998-09-25 | 2000-04-04 | Mitsubishi Heavy Ind Ltd | 排ガスの脱硝方法 |
US6221660B1 (en) * | 1999-02-22 | 2001-04-24 | Synaptic Pharmaceutical Corporation | DNA encoding SNORF25 receptor |
SE9902987D0 (sv) * | 1999-08-24 | 1999-08-24 | Astra Pharma Prod | Novel compounds |
WO2003020217A2 (en) * | 2001-08-31 | 2003-03-13 | University Of Connecticut | Novel pyrazole analogs acting on cannabinoid receptors |
WO2001054503A1 (en) * | 2000-01-28 | 2001-08-02 | Akkadix Corporation | Methods for killing nematodes and nematode eggs using 4-phenoxy-6-aminopyrimidine derivatives |
GB0230045D0 (en) * | 2002-12-23 | 2003-01-29 | Glaxo Group Ltd | Compounds |
US7332508B2 (en) * | 2002-12-18 | 2008-02-19 | Novo Nordisk A/S | Substituted homopiperidine, piperidine or pyrrolidine derivatives |
US7232823B2 (en) * | 2003-06-09 | 2007-06-19 | Pfizer, Inc. | Cannabinoid receptor ligands and uses thereof |
GB0325956D0 (en) * | 2003-11-06 | 2003-12-10 | Addex Pharmaceuticals Sa | Novel compounds |
EP1711491A1 (en) * | 2003-12-24 | 2006-10-18 | Prosidion Limited | Heterocyclic derivatives as gpcr receptor agonists |
-
2006
- 2006-06-29 EP EP06744356A patent/EP1907383A1/en not_active Withdrawn
- 2006-06-29 WO PCT/GB2006/050176 patent/WO2007003960A1/en active Application Filing
- 2006-06-29 US US11/922,765 patent/US20090325924A1/en not_active Abandoned
- 2006-06-29 JP JP2008520006A patent/JP5114395B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US20090325924A1 (en) | 2009-12-31 |
EP1907383A1 (en) | 2008-04-09 |
JP2008545007A (ja) | 2008-12-11 |
WO2007003960A1 (en) | 2007-01-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5114395B2 (ja) | Gpcrアゴニスト | |
JP4958560B2 (ja) | Gpcr受容体作動薬としてのヘテロ環誘導体 | |
EP2013201B1 (en) | Heterocyclic gpcr agonists | |
JP2008545008A (ja) | Gpcrアゴニスト | |
JP4916452B2 (ja) | Gpcr作動薬としてのピリジン、ピリミジン、およびピラジンの誘導体 | |
JP2011500659A (ja) | アゼチジニルgタンパク質共役受容体アゴニスト | |
JP2010514831A (ja) | ピペリジンgpcrアゴニスト | |
JP2010514832A (ja) | ピペリジンgpcrアゴニスト | |
JP2011527334A (ja) | ヘテロ環式gpcr作動薬 | |
JP2009533410A (ja) | Gタンパク質共役型受容体(gpr119)アゴニストとしてのアゼチジン誘導体 | |
JP2010514828A (ja) | ピペリジンgpcrアゴニスト | |
JP2010514830A (ja) | ピペリジンgpcrアゴニスト | |
JP2010514829A (ja) | ピペリジンgpcrアゴニスト | |
JP2008545010A (ja) | Gタンパク質共役受容体アゴニスト | |
JP2011527332A (ja) | ピペリジンgpcr作動薬 | |
JP2011527335A (ja) | ヘテロ環式gpcr作動薬 | |
JP2012211204A (ja) | Gpcrアゴニスト | |
JP2008525417A (ja) | Gタンパク質結合受容体作動薬 | |
JP2011527333A (ja) | ピペリジニルgpcr作動薬 | |
JP2011527331A (ja) | ピペリジニルgpcr作動薬 | |
JP2011500658A (ja) | アゼチジニルgタンパク質共役受容体アゴニスト | |
MXPA06007135A (en) | Heterocyclic derivatives as gpcr receptor agonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090629 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120207 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20120208 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120316 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120326 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120605 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120612 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120806 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120828 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120905 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20121002 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20121015 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20151019 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |