HRP950488A2 - Combination therapy for hypercholesterolemia - Google Patents

Combination therapy for hypercholesterolemia Download PDF

Info

Publication number: HRP950488A2
Authority: HR; Croatia
Prior art keywords: compound; inhibitor; hmg; alkyl; coa reductase
Prior art date: 1994-09-20

Application number

HR08/308,908A

Other languages

English (en)

Croatian (hr)

Inventor

Lee A Morehouse

Original Assignee

Pfizer

Priority date (The priority date 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 date listed.)

1994-09-20

Filing date

1995-09-20

Publication date

1997-08-31

1995-09-20 Application filed by Pfizer filed Critical Pfizer

1997-08-31 Publication of HRP950488A2 publication Critical patent/HRP950488A2/hr

Links

208000035150 Hypercholesterolemia Diseases 0.000 title claims description 14
238000002648 combination therapy Methods 0.000 title description 8
150000001875 compounds Chemical class 0.000 claims description 304
-1 methylene, carbonyl Chemical group 0.000 claims description 138
238000000034 method Methods 0.000 claims description 95
239000002131 composite material Substances 0.000 claims description 74
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 62
239000003112 inhibitor Substances 0.000 claims description 51
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 43
229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 42
239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 42
239000001257 hydrogen Substances 0.000 claims description 39
229910052739 hydrogen Inorganic materials 0.000 claims description 39
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 30
125000003118 aryl group Chemical group 0.000 claims description 26
125000001153 fluoro group Chemical group F* 0.000 claims description 26
108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 claims description 24
235000019000 fluorine Nutrition 0.000 claims description 24
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 23
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
229910052799 carbon Inorganic materials 0.000 claims description 22
229940122502 Cholesterol absorption inhibitor Drugs 0.000 claims description 21
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
229910052736 halogen Inorganic materials 0.000 claims description 20
150000002367 halogens Chemical class 0.000 claims description 20
150000003839 salts Chemical class 0.000 claims description 19
241000124008 Mammalia Species 0.000 claims description 18
239000000203 mixture Substances 0.000 claims description 18
229910052757 nitrogen Inorganic materials 0.000 claims description 18
230000001906 cholesterol absorption Effects 0.000 claims description 17
150000002431 hydrogen Chemical class 0.000 claims description 17
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
102000003960 Ligases Human genes 0.000 claims description 16
108090000364 Ligases Proteins 0.000 claims description 16
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
125000004076 pyridyl group Chemical group 0.000 claims description 16
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
201000001320 Atherosclerosis Diseases 0.000 claims description 15
CAHGCLMLTWQZNJ-RGEKOYMOSA-N lanosterol Chemical compound C([C@]12C)C[C@@H](O)C(C)(C)[C@H]1CCC1=C2CC[C@]2(C)[C@H]([C@H](CCC=C(C)C)C)CC[C@@]21C CAHGCLMLTWQZNJ-RGEKOYMOSA-N 0.000 claims description 15
PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 14
BQPPJGMMIYJVBR-UHFFFAOYSA-N (10S)-3c-Acetoxy-4.4.10r.13c.14t-pentamethyl-17c-((R)-1.5-dimethyl-hexen-(4)-yl)-(5tH)-Delta8-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C BQPPJGMMIYJVBR-UHFFFAOYSA-N 0.000 claims description 13
CHGIKSSZNBCNDW-UHFFFAOYSA-N (3beta,5alpha)-4,4-Dimethylcholesta-8,24-dien-3-ol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21 CHGIKSSZNBCNDW-UHFFFAOYSA-N 0.000 claims description 13
XYTLYKGXLMKYMV-UHFFFAOYSA-N 14alpha-methylzymosterol Natural products CC12CCC(O)CC1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C XYTLYKGXLMKYMV-UHFFFAOYSA-N 0.000 claims description 13
FPTJELQXIUUCEY-UHFFFAOYSA-N 3beta-Hydroxy-lanostan Natural products C1CC2C(C)(C)C(O)CCC2(C)C2C1C1(C)CCC(C(C)CCCC(C)C)C1(C)CC2 FPTJELQXIUUCEY-UHFFFAOYSA-N 0.000 claims description 13
BKLIAINBCQPSOV-UHFFFAOYSA-N Gluanol Natural products CC(C)CC=CC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(O)C(C)(C)C4CC3 BKLIAINBCQPSOV-UHFFFAOYSA-N 0.000 claims description 13
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
LOPKHWOTGJIQLC-UHFFFAOYSA-N Lanosterol Natural products CC(CCC=C(C)C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 LOPKHWOTGJIQLC-UHFFFAOYSA-N 0.000 claims description 13
CAHGCLMLTWQZNJ-UHFFFAOYSA-N Nerifoliol Natural products CC12CCC(O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C CAHGCLMLTWQZNJ-UHFFFAOYSA-N 0.000 claims description 13
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
QBSJHOGDIUQWTH-UHFFFAOYSA-N dihydrolanosterol Natural products CC(C)CCCC(C)C1CCC2(C)C3=C(CCC12C)C4(C)CCC(C)(O)C(C)(C)C4CC3 QBSJHOGDIUQWTH-UHFFFAOYSA-N 0.000 claims description 13
239000003937 drug carrier Substances 0.000 claims description 13
229940058690 lanosterol Drugs 0.000 claims description 13
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 12
125000005236 alkanoylamino group Chemical group 0.000 claims description 12
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 12
125000002541 furyl group Chemical group 0.000 claims description 12
150000004677 hydrates Chemical class 0.000 claims description 12
229960004844 lovastatin Drugs 0.000 claims description 12
PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 12
QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 12
125000000335 thiazolyl group Chemical group 0.000 claims description 12
125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 11
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
229940119502 Squalene cyclase inhibitor Drugs 0.000 claims description 10
229940123185 Squalene epoxidase inhibitor Drugs 0.000 claims description 10
125000003282 alkyl amino group Chemical group 0.000 claims description 10
125000002757 morpholinyl group Chemical group 0.000 claims description 10
125000003386 piperidinyl group Chemical group 0.000 claims description 10
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
239000004059 squalene synthase inhibitor Substances 0.000 claims description 10
125000001544 thienyl group Chemical group 0.000 claims description 10
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 9
TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 9
RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 9
125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 9
125000000217 alkyl group Chemical group 0.000 claims description 9
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
125000000842 isoxazolyl group Chemical group 0.000 claims description 9
229960002965 pravastatin Drugs 0.000 claims description 9
TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 9
229960002855 simvastatin Drugs 0.000 claims description 9
RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 9
XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 8
XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 8
229960005370 atorvastatin Drugs 0.000 claims description 8
GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 claims description 8
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 claims description 8
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
229940032094 squalane Drugs 0.000 claims description 8
238000012546 transfer Methods 0.000 claims description 8
229940122680 Demethylase inhibitor Drugs 0.000 claims description 7
229940123495 Squalene synthetase inhibitor Drugs 0.000 claims description 7
125000001041 indolyl group Chemical group 0.000 claims description 7
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
125000000168 pyrrolyl group Chemical group 0.000 claims description 7
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims description 6
125000004414 alkyl thio group Chemical group 0.000 claims description 6
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 6
125000000623 heterocyclic group Chemical group 0.000 claims description 6
125000002883 imidazolyl group Chemical group 0.000 claims description 6
125000001786 isothiazolyl group Chemical group 0.000 claims description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
125000002971 oxazolyl group Chemical group 0.000 claims description 6
125000003226 pyrazolyl group Chemical group 0.000 claims description 6
125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 5
125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 4
KGJWJWANAXKLRA-ISKFKSNPSA-N 2-[(3r,5r)-7-chloro-1-(2,2-dimethylpropyl)-5-naphthalen-1-yl-2-oxo-5h-4,1-benzothiazepin-3-yl]acetic acid Chemical compound S1[C@H](CC(O)=O)C(=O)N(CC(C)(C)C)C2=CC=C(Cl)C=C2[C@H]1C1=CC=CC2=CC=CC=C12 KGJWJWANAXKLRA-ISKFKSNPSA-N 0.000 claims description 4
UWAPIZBSXPPGGH-ISKFKSNPSA-N 2-[(3r,5r)-7-chloro-1-(2,2-dimethylpropyl)-5-naphthalen-1-yl-2-oxo-5h-4,1-benzoxazepin-3-yl]acetic acid Chemical compound O1[C@H](CC(O)=O)C(=O)N(CC(C)(C)C)C2=CC=C(Cl)C=C2[C@H]1C1=CC=CC2=CC=CC=C12 UWAPIZBSXPPGGH-ISKFKSNPSA-N 0.000 claims description 4
125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 4
SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 4
125000001488 beta-D-galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims description 4
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 3
125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 3
KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 3
125000003545 alkoxy group Chemical group 0.000 claims description 3
125000000129 anionic group Chemical group 0.000 claims description 3
125000002091 cationic group Chemical group 0.000 claims description 3
125000004122 cyclic group Chemical group 0.000 claims description 3
125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 3
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
125000003431 oxalo group Chemical group 0.000 claims description 3
125000004193 piperazinyl group Chemical group 0.000 claims description 3
239000000651 prodrug Substances 0.000 claims description 3
229940002612 prodrug Drugs 0.000 claims description 3
125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
229920006395 saturated elastomer Polymers 0.000 claims description 3
125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 3
ANJHPXLVGHXNQU-PJMJKUDTSA-N (1R,2S,4S,5'R,6R,7S,8R,9S,12S,13S)-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.02,9.04,8.013,18]icosane-6,2'-oxane]-10-one Chemical compound O([C@@H]1[C@@H]([C@]2(C(=O)C[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 ANJHPXLVGHXNQU-PJMJKUDTSA-N 0.000 claims description 2
125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 2
125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
229910052731 fluorine Inorganic materials 0.000 claims description 2
239000011737 fluorine Substances 0.000 claims description 2
125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
125000004043 oxo group Chemical group O=* 0.000 claims description 2
125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
125000001183 hydrocarbyl group Chemical group 0.000 claims 1
125000003396 thiol group Chemical group [H]S* 0.000 claims 1
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 128
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
230000000875 corresponding effect Effects 0.000 description 50
150000003431 steroids Chemical group 0.000 description 43
235000012000 cholesterol Nutrition 0.000 description 36
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
239000002904 solvent Substances 0.000 description 28
239000002253 acid Substances 0.000 description 27
238000006243 chemical reaction Methods 0.000 description 26
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
150000001412 amines Chemical class 0.000 description 23
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
230000000694 effects Effects 0.000 description 20
239000000010 aprotic solvent Substances 0.000 description 19
239000003795 chemical substances by application Substances 0.000 description 19
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
235000005911 diet Nutrition 0.000 description 18
230000037213 diet Effects 0.000 description 18
238000002360 preparation method Methods 0.000 description 18
241000282414 Homo sapiens Species 0.000 description 16
230000015572 biosynthetic process Effects 0.000 description 16
125000006239 protecting group Chemical group 0.000 description 16
239000007858 starting material Substances 0.000 description 16
241000699800 Cricetinae Species 0.000 description 15
102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 15
230000009467 reduction Effects 0.000 description 15
238000006722 reduction reaction Methods 0.000 description 15
238000003786 synthesis reaction Methods 0.000 description 15
229930182558 Sterol Natural products 0.000 description 14
235000003702 sterols Nutrition 0.000 description 14
230000002829 reductive effect Effects 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
210000004185 liver Anatomy 0.000 description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
229930002534 steroid glycoside Natural products 0.000 description 12
150000003432 sterols Chemical class 0.000 description 12
230000008878 coupling Effects 0.000 description 11
238000010168 coupling process Methods 0.000 description 11
238000005859 coupling reaction Methods 0.000 description 11
239000012442 inert solvent Substances 0.000 description 11
239000008194 pharmaceutical composition Substances 0.000 description 11
238000010992 reflux Methods 0.000 description 11
229940123239 Cholesterol synthesis inhibitor Drugs 0.000 description 10
102000005782 Squalene Monooxygenase Human genes 0.000 description 10
230000007935 neutral effect Effects 0.000 description 10
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
230000010933 acylation Effects 0.000 description 9
238000005917 acylation reaction Methods 0.000 description 9
230000005764 inhibitory process Effects 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
238000010561 standard procedure Methods 0.000 description 9
CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 8
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
241001465754 Metazoa Species 0.000 description 8
150000001408 amides Chemical class 0.000 description 8
239000003054 catalyst Substances 0.000 description 8
230000000055 hyoplipidemic effect Effects 0.000 description 8
239000000543 intermediate Substances 0.000 description 8
239000012948 isocyanate Substances 0.000 description 8
150000002513 isocyanates Chemical class 0.000 description 8
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
BHHYHSUAOQUXJK-UHFFFAOYSA-L zinc fluoride Chemical compound F[Zn]F BHHYHSUAOQUXJK-UHFFFAOYSA-L 0.000 description 8
229940127328 Cholesterol Synthesis Inhibitors Drugs 0.000 description 7
241000282412 Homo Species 0.000 description 7
125000002252 acyl group Chemical group 0.000 description 7
230000007062 hydrolysis Effects 0.000 description 7
238000006460 hydrolysis reaction Methods 0.000 description 7
239000012280 lithium aluminium hydride Substances 0.000 description 7
238000006884 silylation reaction Methods 0.000 description 7
239000000243 solution Substances 0.000 description 7
102000030633 squalene cyclase Human genes 0.000 description 7
108010088324 squalene cyclase Proteins 0.000 description 7
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
230000002378 acidificating effect Effects 0.000 description 6
230000003197 catalytic effect Effects 0.000 description 6
208000029078 coronary artery disease Diseases 0.000 description 6
210000003608 fece Anatomy 0.000 description 6
238000001914 filtration Methods 0.000 description 6
229910052744 lithium Inorganic materials 0.000 description 6
150000002825 nitriles Chemical class 0.000 description 6
229910000027 potassium carbonate Inorganic materials 0.000 description 6
238000001556 precipitation Methods 0.000 description 6
LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 6
238000002560 therapeutic procedure Methods 0.000 description 6
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 5
102000004190 Enzymes Human genes 0.000 description 5
108090000790 Enzymes Proteins 0.000 description 5
108020003891 Squalene monooxygenase Proteins 0.000 description 5
239000008280 blood Substances 0.000 description 5
210000004369 blood Anatomy 0.000 description 5
238000007796 conventional method Methods 0.000 description 5
230000029142 excretion Effects 0.000 description 5
238000001030 gas--liquid chromatography Methods 0.000 description 5
150000002632 lipids Chemical class 0.000 description 5
230000004060 metabolic process Effects 0.000 description 5
TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 5
230000003228 microsomal effect Effects 0.000 description 5
230000003647 oxidation Effects 0.000 description 5
238000007254 oxidation reaction Methods 0.000 description 5
210000000813 small intestine Anatomy 0.000 description 5
238000003756 stirring Methods 0.000 description 5
238000006467 substitution reaction Methods 0.000 description 5
210000001519 tissue Anatomy 0.000 description 5
KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 4
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 4
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
241000283973 Oryctolagus cuniculus Species 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 4
230000001476 alcoholic effect Effects 0.000 description 4
229910021529 ammonia Inorganic materials 0.000 description 4
238000004458 analytical method Methods 0.000 description 4
230000033228 biological regulation Effects 0.000 description 4
150000001718 carbodiimides Chemical class 0.000 description 4
239000003638 chemical reducing agent Substances 0.000 description 4
229940117975 chromium trioxide Drugs 0.000 description 4
WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 4
150000002148 esters Chemical class 0.000 description 4
230000002349 favourable effect Effects 0.000 description 4
230000002550 fecal effect Effects 0.000 description 4
150000004820 halides Chemical class 0.000 description 4
230000026030 halogenation Effects 0.000 description 4
238000005658 halogenation reaction Methods 0.000 description 4
238000005907 ketalization reaction Methods 0.000 description 4
239000007788 liquid Substances 0.000 description 4
PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
239000000312 peanut oil Substances 0.000 description 4
239000011541 reaction mixture Substances 0.000 description 4
238000009097 single-agent therapy Methods 0.000 description 4
239000007787 solid Substances 0.000 description 4
229940031439 squalene Drugs 0.000 description 4
TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 4
239000000725 suspension Substances 0.000 description 4
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 3
YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 3
QYIMSPSDBYKPPY-RSKUXYSASA-N (S)-2,3-epoxysqualene Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C=C(/C)CC\C=C(/C)CC[C@@H]1OC1(C)C QYIMSPSDBYKPPY-RSKUXYSASA-N 0.000 description 3
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
RTKMFQOHBDVEBC-UHFFFAOYSA-N 3-bromo-3-buten-1-ol Chemical compound OCCC(Br)=C RTKMFQOHBDVEBC-UHFFFAOYSA-N 0.000 description 3
XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 3
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
241000699673 Mesocricetus auratus Species 0.000 description 3
102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 3
235000019483 Peanut oil Nutrition 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
150000001241 acetals Chemical class 0.000 description 3
239000003524 antilipemic agent Substances 0.000 description 3
210000000709 aorta Anatomy 0.000 description 3
239000012736 aqueous medium Substances 0.000 description 3
239000007864 aqueous solution Substances 0.000 description 3
150000001540 azides Chemical group 0.000 description 3
239000000872 buffer Substances 0.000 description 3
239000002775 capsule Substances 0.000 description 3
230000021235 carbamoylation Effects 0.000 description 3
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
150000001840 cholesterol esters Chemical class 0.000 description 3
230000006196 deacetylation Effects 0.000 description 3
238000003381 deacetylation reaction Methods 0.000 description 3
230000007423 decrease Effects 0.000 description 3
238000010511 deprotection reaction Methods 0.000 description 3
239000003814 drug Substances 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
230000008020 evaporation Effects 0.000 description 3
229960003765 fluvastatin Drugs 0.000 description 3
235000013305 food Nutrition 0.000 description 3
238000004108 freeze drying Methods 0.000 description 3
230000002440 hepatic effect Effects 0.000 description 3
230000000260 hypercholesteremic effect Effects 0.000 description 3
210000000936 intestine Anatomy 0.000 description 3
238000004519 manufacturing process Methods 0.000 description 3
229940075610 mercuric cyanide Drugs 0.000 description 3
244000005700 microbiome Species 0.000 description 3
150000004002 naphthaldehydes Chemical class 0.000 description 3
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
238000011587 new zealand white rabbit Methods 0.000 description 3
150000002923 oximes Chemical class 0.000 description 3
229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 3
239000003880 polar aprotic solvent Substances 0.000 description 3
239000000843 powder Substances 0.000 description 3
230000008569 process Effects 0.000 description 3
102000004169 proteins and genes Human genes 0.000 description 3
108090000623 proteins and genes Proteins 0.000 description 3
238000007127 saponification reaction Methods 0.000 description 3
108010019261 squalene epoxidase-cyclase Proteins 0.000 description 3
230000003637 steroidlike Effects 0.000 description 3
230000002195 synergetic effect Effects 0.000 description 3
239000003826 tablet Substances 0.000 description 3
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
230000001225 therapeutic effect Effects 0.000 description 3
150000003952 β-lactams Chemical class 0.000 description 3
KQBWAWQIKFPGCL-TZXAIGQNSA-N (1S,2S,4S,5'R,6R,7S,8R,9S,12S,13S)-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.02,9.04,8.013,18]icosane-6,2'-oxane]-11-one Chemical compound O([C@@H]1[C@@H]([C@]2(CC(=O)[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 KQBWAWQIKFPGCL-TZXAIGQNSA-N 0.000 description 2
ZLYYJUJDFKGVKB-OWOJBTEDSA-N (e)-but-2-enedioyl dichloride Chemical compound ClC(=O)\C=C\C(Cl)=O ZLYYJUJDFKGVKB-OWOJBTEDSA-N 0.000 description 2
YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical class NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
206010002091 Anaesthesia Diseases 0.000 description 2
208000024172 Cardiovascular disease Diseases 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
108010089254 Cholesterol oxidase Proteins 0.000 description 2
229940126062 Compound A Drugs 0.000 description 2
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
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 2
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
108090001030 Lipoproteins Proteins 0.000 description 2
102000004895 Lipoproteins Human genes 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
GMBQZIIUCVWOCD-WWASVFFGSA-N Sarsapogenine Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@H](C)CO1 GMBQZIIUCVWOCD-WWASVFFGSA-N 0.000 description 2
108010055297 Sterol Esterase Proteins 0.000 description 2
102000000019 Sterol Esterase Human genes 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
RTMWIZOXNKJHRE-UHFFFAOYSA-N Tigogenin Natural products CC1COC2CC(C)(OC12)C3CCC4C5CCC6CC(O)CCC6(C)C5CCC34C RTMWIZOXNKJHRE-UHFFFAOYSA-N 0.000 description 2
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
RCHRXNVVPVVBAV-SUPLOUSYSA-N [(6e,10e,14e,18e)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaenoxy]cyclopropane Chemical class CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C=C(/C)CC\C=C(/C)CCC=C(C)COC1CC1 RCHRXNVVPVVBAV-SUPLOUSYSA-N 0.000 description 2
230000009102 absorption Effects 0.000 description 2
238000010521 absorption reaction Methods 0.000 description 2
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
229940100228 acetyl coenzyme a Drugs 0.000 description 2
150000008065 acid anhydrides Chemical class 0.000 description 2
239000013543 active substance Substances 0.000 description 2
150000001350 alkyl halides Chemical class 0.000 description 2
230000029936 alkylation Effects 0.000 description 2
238000005804 alkylation reaction Methods 0.000 description 2
QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-N 0.000 description 2
235000019270 ammonium chloride Nutrition 0.000 description 2
230000037005 anaesthesia Effects 0.000 description 2
238000010171 animal model Methods 0.000 description 2
239000003613 bile acid Substances 0.000 description 2
229920000080 bile acid sequestrant Polymers 0.000 description 2
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
150000001721 carbon Chemical group 0.000 description 2
150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
239000000969 carrier Substances 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
238000006567 deketalization reaction Methods 0.000 description 2
230000008021 deposition Effects 0.000 description 2
RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 2
CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
201000010099 disease Diseases 0.000 description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
238000006345 epimerization reaction Methods 0.000 description 2
238000010931 ester hydrolysis Methods 0.000 description 2
238000010575 fractional recrystallization Methods 0.000 description 2
125000000524 functional group Chemical group 0.000 description 2
229930182478 glucoside Natural products 0.000 description 2
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 2
150000002430 hydrocarbons Chemical group 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
238000011534 incubation Methods 0.000 description 2
230000006698 induction Effects 0.000 description 2
238000002955 isolation Methods 0.000 description 2
125000000468 ketone group Chemical group 0.000 description 2
150000002576 ketones Chemical class 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
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
230000014759 maintenance of location Effects 0.000 description 2
NGYIMTKLQULBOO-UHFFFAOYSA-L mercury dibromide Chemical compound Br[Hg]Br NGYIMTKLQULBOO-UHFFFAOYSA-L 0.000 description 2
229910052751 metal Inorganic materials 0.000 description 2
239000002184 metal Substances 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
239000002245 particle Substances 0.000 description 2
230000037361 pathway Effects 0.000 description 2
150000004965 peroxy acids Chemical class 0.000 description 2
239000006187 pill Substances 0.000 description 2
230000036470 plasma concentration Effects 0.000 description 2
239000002798 polar solvent Substances 0.000 description 2
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
230000001681 protective effect Effects 0.000 description 2
238000006268 reductive amination reaction Methods 0.000 description 2
230000004044 response Effects 0.000 description 2
238000012552 review Methods 0.000 description 2
238000007363 ring formation reaction Methods 0.000 description 2
NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
239000012279 sodium borohydride Substances 0.000 description 2
229910000033 sodium borohydride Inorganic materials 0.000 description 2
150000008143 steroidal glycosides Chemical class 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
229940124597 therapeutic agent Drugs 0.000 description 2
238000004809 thin layer chromatography Methods 0.000 description 2
CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
150000003573 thiols Chemical group 0.000 description 2
238000013518 transcription Methods 0.000 description 2
230000035897 transcription Effects 0.000 description 2
238000013519 translation Methods 0.000 description 2
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 1
XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 description 1
XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 description 1
RWIUTHWKQHRQNP-ZDVGBALWSA-N (9e,12e)-n-(1-phenylethyl)octadeca-9,12-dienamide Chemical compound CCCCC\C=C\C\C=C\CCCCCCCC(=O)NC(C)C1=CC=CC=C1 RWIUTHWKQHRQNP-ZDVGBALWSA-N 0.000 description 1
HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 1
OKZYCXHTTZZYSK-ZCFIWIBFSA-N (R)-5-phosphomevalonic acid Chemical compound OC(=O)C[C@@](O)(C)CCOP(O)(O)=O OKZYCXHTTZZYSK-ZCFIWIBFSA-N 0.000 description 1
XLYMOEINVGRTEX-ONEGZZNKSA-N (e)-4-ethoxy-4-oxobut-2-enoic acid Chemical compound CCOC(=O)\C=C\C(O)=O XLYMOEINVGRTEX-ONEGZZNKSA-N 0.000 description 1
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
NNHYAHOTXLASEA-UHFFFAOYSA-N 1-(dimethoxymethyl)-4-methoxybenzene Chemical compound COC(OC)C1=CC=C(OC)C=C1 NNHYAHOTXLASEA-UHFFFAOYSA-N 0.000 description 1
NUVNTLUAKVBWFN-UHFFFAOYSA-N 1-[1-(3-methylbutylsulfinyl)pentan-2-yl]piperidine Chemical compound CC(C)CCS(=O)CC(CCC)N1CCCCC1 NUVNTLUAKVBWFN-UHFFFAOYSA-N 0.000 description 1
JKHVMHRZELZAMB-UHFFFAOYSA-N 1-[2-(2-piperidin-1-ylethylsulfanyl)ethyl]piperidine Chemical compound C1CCCCN1CCSCCN1CCCCC1 JKHVMHRZELZAMB-UHFFFAOYSA-N 0.000 description 1
ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
YVTPINJIEGFACL-UHFFFAOYSA-N 1-piperidin-1-yloxypiperidine Chemical class C1CCCCN1ON1CCCCC1 YVTPINJIEGFACL-UHFFFAOYSA-N 0.000 description 1
URRQEBTVGCKANT-UHFFFAOYSA-N 2-methyl-2-piperidin-4-ylpropan-1-ol Chemical compound OCC(C)(C)C1CCNCC1 URRQEBTVGCKANT-UHFFFAOYSA-N 0.000 description 1
XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 1
JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical class OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-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
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
IZVFFXVYBHFIHY-SKCNUYALSA-N 5alpha-cholest-7-en-3beta-ol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CCCC(C)C)CC[C@H]33)C)C3=CC[C@H]21 IZVFFXVYBHFIHY-SKCNUYALSA-N 0.000 description 1
PESKGJQREUXSRR-UXIWKSIVSA-N 5alpha-cholestan-3-one Chemical compound C([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 PESKGJQREUXSRR-UXIWKSIVSA-N 0.000 description 1
PESKGJQREUXSRR-UHFFFAOYSA-N 5beta-cholestanone Natural products C1CC2CC(=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 PESKGJQREUXSRR-UHFFFAOYSA-N 0.000 description 1
XIIAYQZJNBULGD-XWLABEFZSA-N 5α-cholestane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 XIIAYQZJNBULGD-XWLABEFZSA-N 0.000 description 1
102100031126 6-phosphogluconolactonase Human genes 0.000 description 1
108010029731 6-phosphogluconolactonase Proteins 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
101710095342 Apolipoprotein B Proteins 0.000 description 1
102100040202 Apolipoprotein B-100 Human genes 0.000 description 1
102000006410 Apoproteins Human genes 0.000 description 1
108010083590 Apoproteins Proteins 0.000 description 1
206010003210 Arteriosclerosis Diseases 0.000 description 1
241000228212 Aspergillus Species 0.000 description 1
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
241000283153 Cetacea Species 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
101710095468 Cyclase Proteins 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
241000196324 Embryophyta Species 0.000 description 1
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
239000005977 Ethylene Substances 0.000 description 1
VWFJDQUYCIWHTN-UHFFFAOYSA-N Farnesyl pyrophosphate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOP(O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-UHFFFAOYSA-N 0.000 description 1
108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 description 1
238000005727 Friedel-Crafts reaction Methods 0.000 description 1
HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 description 1
108010023302 HDL Cholesterol Proteins 0.000 description 1
108010010234 HDL Lipoproteins Proteins 0.000 description 1
102000015779 HDL Lipoproteins Human genes 0.000 description 1
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical class CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
240000007049 Juglans regia Species 0.000 description 1
235000009496 Juglans regia Nutrition 0.000 description 1
229930194542 Keto Natural products 0.000 description 1
108010007622 LDL Lipoproteins Proteins 0.000 description 1
102000007330 LDL Lipoproteins Human genes 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
239000002841 Lewis acid Substances 0.000 description 1
229930195725 Mannitol Natural products 0.000 description 1
239000012359 Methanesulfonyl chloride Substances 0.000 description 1
LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
229930193140 Neomycin Natural products 0.000 description 1
102000004316 Oxidoreductases Human genes 0.000 description 1
108090000854 Oxidoreductases Proteins 0.000 description 1
208000018262 Peripheral vascular disease Diseases 0.000 description 1
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
241000283984 Rodentia Species 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
229920002472 Starch Polymers 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
238000006859 Swern oxidation reaction Methods 0.000 description 1
239000007983 Tris buffer Substances 0.000 description 1
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
NAJPJPDKEMVUIU-UHFFFAOYSA-N [17-(5-ethyl-6-methylheptan-2-yl)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound C1CC2CC(OP([O-])(=O)OCC[N+](C)(C)C)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 NAJPJPDKEMVUIU-UHFFFAOYSA-N 0.000 description 1
XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 description 1
238000002835 absorbance Methods 0.000 description 1
238000009825 accumulation Methods 0.000 description 1
OJFDKHTZOUZBOS-CITAKDKDSA-N acetoacetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 OJFDKHTZOUZBOS-CITAKDKDSA-N 0.000 description 1
230000021736 acetylation Effects 0.000 description 1
238000006640 acetylation reaction Methods 0.000 description 1
239000003377 acid catalyst Substances 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
230000003213 activating effect Effects 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
150000004703 alkoxides Chemical class 0.000 description 1
125000004849 alkoxymethyl group Chemical group 0.000 description 1
125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 description 1
125000005103 alkyl silyl group Chemical group 0.000 description 1
125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
230000002152 alkylating effect Effects 0.000 description 1
150000001414 amino alcohols Chemical class 0.000 description 1
125000003277 amino group Chemical group 0.000 description 1
150000001450 anions Chemical class 0.000 description 1
230000000879 anti-atherosclerotic effect Effects 0.000 description 1
239000003529 anticholesteremic agent Substances 0.000 description 1
208000011775 arteriosclerosis disease Diseases 0.000 description 1
125000005002 aryl methyl group Chemical group 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
150000003851 azoles Chemical class 0.000 description 1
230000009286 beneficial effect Effects 0.000 description 1
AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
229940076810 beta sitosterol Drugs 0.000 description 1
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
229940096699 bile acid sequestrants Drugs 0.000 description 1
230000001851 biosynthetic effect Effects 0.000 description 1
230000000903 blocking effect Effects 0.000 description 1
229910000085 borane Inorganic materials 0.000 description 1
MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
230000031709 bromination Effects 0.000 description 1
238000005893 bromination reaction Methods 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
239000004202 carbamide Substances 0.000 description 1
239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
230000006315 carbonylation Effects 0.000 description 1
238000005810 carbonylation reaction Methods 0.000 description 1
125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
150000003857 carboxamides Chemical class 0.000 description 1
125000004181 carboxyalkyl group Chemical group 0.000 description 1
150000001735 carboxylic acids Chemical class 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
238000006555 catalytic reaction Methods 0.000 description 1
150000001768 cations Chemical class 0.000 description 1
238000004113 cell culture Methods 0.000 description 1
230000001413 cellular effect Effects 0.000 description 1
239000001913 cellulose Substances 0.000 description 1
229920002678 cellulose Polymers 0.000 description 1
230000002490 cerebral effect Effects 0.000 description 1
150000001805 chlorine compounds Chemical class 0.000 description 1
150000001841 cholesterols Chemical class 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
230000002301 combined effect Effects 0.000 description 1
238000009833 condensation Methods 0.000 description 1
230000005494 condensation Effects 0.000 description 1
230000001276 controlling effect Effects 0.000 description 1
239000012059 conventional drug carrier Substances 0.000 description 1
ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
QYIXCDOBOSTCEI-NWKZBHTNSA-N coprostanol Chemical compound C([C@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-NWKZBHTNSA-N 0.000 description 1
238000012937 correction Methods 0.000 description 1
230000002596 correlated effect Effects 0.000 description 1
239000007822 coupling agent Substances 0.000 description 1
238000012258 culturing Methods 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
238000010520 demethylation reaction Methods 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
238000005828 desilylation reaction Methods 0.000 description 1
238000011161 development Methods 0.000 description 1
239000012975 dibutyltin dilaurate Substances 0.000 description 1
ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
238000001085 differential centrifugation Methods 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
150000004862 dioxolanes Chemical class 0.000 description 1
229910001882 dioxygen Inorganic materials 0.000 description 1
VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
230000002526 effect on cardiovascular system Effects 0.000 description 1
238000005516 engineering process Methods 0.000 description 1
238000006911 enzymatic reaction Methods 0.000 description 1
108010017796 epoxidase Proteins 0.000 description 1
125000001033 ether group Chemical group 0.000 description 1
238000006266 etherification reaction Methods 0.000 description 1
239000000284 extract Substances 0.000 description 1
238000000605 extraction Methods 0.000 description 1
238000000855 fermentation Methods 0.000 description 1
230000004151 fermentation Effects 0.000 description 1
239000012530 fluid Substances 0.000 description 1
239000012025 fluorinating agent Substances 0.000 description 1
238000003682 fluorination reaction Methods 0.000 description 1
230000004907 flux Effects 0.000 description 1
238000009472 formulation Methods 0.000 description 1
XLYMOEINVGRTEX-UHFFFAOYSA-N fumaric acid monoethyl ester Natural products CCOC(=O)C=CC(O)=O XLYMOEINVGRTEX-UHFFFAOYSA-N 0.000 description 1
210000001035 gastrointestinal tract Anatomy 0.000 description 1
229960003627 gemfibrozil Drugs 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
150000008131 glucosides Chemical class 0.000 description 1
150000004676 glycans Chemical class 0.000 description 1
229930182470 glycoside Natural products 0.000 description 1
150000002338 glycosides Chemical class 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
229920000669 heparin Polymers 0.000 description 1
229960002897 heparin Drugs 0.000 description 1
125000005842 heteroatom Chemical group 0.000 description 1
OHYHWAITIOIHFP-UHFFFAOYSA-L hexadecyl(trimethyl)azanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCCCCCCCCCCCCCC[N+](C)(C)C.CCCCCCCCCCCCCCCC[N+](C)(C)C OHYHWAITIOIHFP-UHFFFAOYSA-L 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
150000002440 hydroxy compounds Chemical class 0.000 description 1
LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
238000009169 immunotherapy Methods 0.000 description 1
150000002475 indoles Chemical class 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
239000003999 initiator Substances 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
230000000968 intestinal effect Effects 0.000 description 1
230000026045 iodination Effects 0.000 description 1
238000006192 iodination reaction Methods 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
239000011630 iodine Substances 0.000 description 1
229960004125 ketoconazole Drugs 0.000 description 1
150000003951 lactams Chemical group 0.000 description 1
239000008101 lactose Substances 0.000 description 1
150000007517 lewis acids Chemical class 0.000 description 1
UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
210000001853 liver microsome Anatomy 0.000 description 1
210000005228 liver tissue Anatomy 0.000 description 1
238000011068 loading method Methods 0.000 description 1
ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
239000001095 magnesium carbonate Substances 0.000 description 1
229910000021 magnesium carbonate Inorganic materials 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
239000000594 mannitol Substances 0.000 description 1
235000010355 mannitol Nutrition 0.000 description 1
238000005259 measurement Methods 0.000 description 1
229950008446 melinamide Drugs 0.000 description 1
108020004999 messenger RNA Proteins 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical class C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
239000011707 mineral Substances 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
238000002156 mixing Methods 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
150000004682 monohydrates Chemical class 0.000 description 1
229960004927 neomycin Drugs 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
229910000510 noble metal Inorganic materials 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
230000000269 nucleophilic effect Effects 0.000 description 1
239000006186 oral dosage form Substances 0.000 description 1
229910000489 osmium tetroxide Inorganic materials 0.000 description 1
150000002921 oxetanes Chemical class 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
239000001301 oxygen Substances 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
238000006213 oxygenation reaction Methods 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
239000006201 parenteral dosage form Substances 0.000 description 1
239000008188 pellet Substances 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
239000008177 pharmaceutical agent Substances 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
230000004962 physiological condition Effects 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920001282 polysaccharide Polymers 0.000 description 1
239000005017 polysaccharide Substances 0.000 description 1
230000001376 precipitating effect Effects 0.000 description 1
230000002265 prevention Effects 0.000 description 1
235000019260 propionic acid Nutrition 0.000 description 1
238000010926 purge Methods 0.000 description 1
238000011002 quantification Methods 0.000 description 1
125000001453 quaternary ammonium group Chemical group 0.000 description 1
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
230000009103 reabsorption Effects 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
229930182490 saponin Natural products 0.000 description 1
150000007949 saponins Chemical class 0.000 description 1
235000017709 saponins Nutrition 0.000 description 1
230000007017 scission Effects 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
230000028327 secretion Effects 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
229910001923 silver oxide Inorganic materials 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
229950005143 sitosterol Drugs 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 1
239000012453 solvate Substances 0.000 description 1
LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical class C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
238000010186 staining Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000000758 substrate Substances 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000012622 synthetic inhibitor Substances 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Substances [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
150000003536 tetrazoles Chemical class 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
NJRXVEJTAYWCQJ-UHFFFAOYSA-N thiomalic acid Chemical compound OC(=O)CC(S)C(O)=O NJRXVEJTAYWCQJ-UHFFFAOYSA-N 0.000 description 1
ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
210000000115 thoracic cavity Anatomy 0.000 description 1
230000002103 transcriptional effect Effects 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
239000005051 trimethylchlorosilane Substances 0.000 description 1
FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
230000002792 vascular Effects 0.000 description 1
235000020234 walnut Nutrition 0.000 description 1
239000011701 zinc Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- 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

Landscapes

Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmacology & Pharmacy (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Epidemiology (AREA)
Organic Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Diabetes (AREA)
Hematology (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Medicines Containing Material From Animals Or Micro-Organisms (AREA)

HR08/308,908A 1994-09-20 1995-09-20 Combination therapy for hypercholesterolemia HRP950488A2 (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US30890894A	1994-09-20	1994-09-20

Publications (1)

Publication Number	Publication Date
HRP950488A2 true HRP950488A2 (en)	1997-08-31

Family

ID=23195885

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
HR08/308,908A HRP950488A2 (en)	1994-09-20	1995-09-20	Combination therapy for hypercholesterolemia

Country Status (12)

Country	Link
US (1)	US5807834A (es)
EP (1)	EP0782451A1 (es)
JP (1)	JPH09511753A (es)
AU (1)	AU2453295A (es)
BR (1)	BR9504072A (es)
CA (1)	CA2200436A1 (es)
FI (1)	FI971151A (es)
HR (1)	HRP950488A2 (es)
IL (1)	IL115310A0 (es)
MX (1)	MX9702175A (es)
WO (1)	WO1996009827A2 (es)
ZA (1)	ZA957879B (es)

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
AU7948394A (en) *	1993-12-28	1995-07-17	Pfizer Inc.	Hypocholesterolemic agents
WO1996020184A1 (en) *	1994-12-23	1996-07-04	Pfizer Inc.	Naphthyl-benzoxazepines or -benzothiazepines as squalene synthetase inhibitors
US5965553A (en) *	1996-06-20	1999-10-12	Pfizer Inc.	Squalene synthetase inhibitors
US6537987B1 (en) *	1996-06-20	2003-03-25	Pfizer Inc.	4,1-benzoxazepines or 4,1-benzothiazepines and their use as squalene synthetase inhibitors
ATE309993T1 (de)	1997-04-21	2005-12-15	Takeda Pharmaceutical	4,1-benzoxazepine, ihre analoga, und ihre verwendung als somatostatin-agonisten
US6180660B1 (en) *	1997-08-26	2001-01-30	Merck & Co., Inc.	Cholesterol-lowering therapy
US20030153541A1 (en) *	1997-10-31	2003-08-14	Robert Dudley	Novel anticholesterol compositions and method for using same
GB9923076D0 (en) *	1999-09-29	1999-12-01	Phytopharm Plc	Sapogenin derivatives and their use
PL207723B1 (pl) *	1998-03-26	2011-01-31	Phytopharm Plc	Zastosowanie smilageniny do leczenia choroby Parkinsona
US6207664B1 (en)	1998-11-25	2001-03-27	Pfizer Inc.	Squalene synthetase inhibitor agents
GB9923078D0 (en) *	1999-09-29	1999-12-01	Phytopharm Plc	Sapogenin derivatives and their use
US6465011B2 (en)	1999-05-29	2002-10-15	Abbott Laboratories	Formulations comprising lipid-regulating agents
US6372251B2 (en)	1999-06-11	2002-04-16	Abbott Laboratories	Formulations comprising lipid-regulating agents
GB9923077D0 (en) *	1999-09-29	1999-12-01	Phytopharm Plc	Sapogenin derivatives and their use
GB0000228D0 (en) *	2000-01-06	2000-03-01	Phytopharm Plc	Fluoro substituted sapogenins and their use
US20030092745A1 (en) *	2000-02-25	2003-05-15	Pfizer Inc.	Combination therapy
GB0107822D0 (en) *	2001-03-28	2001-05-23	Phytopharm Plc	Sapogenin derivatives their synthesis and use methods based upon their use
KR101130212B1 (ko) *	2002-03-27	2012-04-13	파이토팜 피엘씨	사포게닌 및 그 유도체의 치료 방법 및 사용법
US20050130948A1 (en) *	2002-03-27	2005-06-16	Daryl Rees	Therapeutic methods and uses of sapogenins and their derivatives
GB0215579D0 (en)	2002-07-05	2002-08-14	Astrazeneca Ab	Chemical compounds
AR040588A1 (es)	2002-07-26	2005-04-13	Schering Corp	Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa
TWI334781B (en) *	2002-10-28	2010-12-21	Phytopharm Plc	Stereospecific synthesis of sapogenins
ATE406364T1 (de)	2003-03-07	2008-09-15	Schering Corp	Substituierte azetidinon-derivate, deren pharmazeutische formulierungen und deren verwendung zur behandlung von hypercholesterolemia
JP4589919B2 (ja)	2003-03-07	2010-12-01	シェーリングコーポレイション	高コレステロール血症の処置のための、置換アゼチジノン化合物、これらの処方物および使用
CN1882327A (zh)	2003-11-19	2006-12-20	症变治疗公司	含磷的新的拟甲状腺素药
DE602004029715D1 (de)	2003-12-23	2010-12-02	Astrazeneca Ab	Diphenylazetidinonderivate mit die cholesterinabsorption hemmender wirkung
JP4477474B2 (ja) *	2004-11-15	2010-06-09	株式会社日立製作所	糞便懸濁ろ過用容器
SA06270191B1 (ar)	2005-06-22	2010-03-29	استرازينيكا ايه بي	مشتقات من 2- أزيتيدينون جديدة باعتبارها مثبطات لامتصاص الكوليسترول لعلاج حالات فرط نسبة الدهون في الدم
CN101291662A (zh)	2005-10-21	2008-10-22	诺瓦提斯公司	肾素抑制剂和抗血脂异常剂和/或抗肥胖剂的组合
AR060623A1 (es)	2006-04-27	2008-07-02	Astrazeneca Ab	Compuestos derivados de 2-azetidinona y un metodo de preparacion
US20100092479A1 (en) *	2008-08-18	2010-04-15	Combinatorx (Singapore) Pte. Ltd.	Compositions and methods for treatment of viral diseases
WO2010093601A1 (en)	2009-02-10	2010-08-19	Metabasis Therapeutics, Inc.	Novel sulfonic acid-containing thyromimetics, and methods for their use
US20130156720A1 (en)	2010-08-27	2013-06-20	Ironwood Pharmaceuticals, Inc.	Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4602005A (en) *	1982-05-17	1986-07-22	Medical Research Foundation Of Oregon	Tigogenin cellobioside for treating hypercholesterolemia and atherosclerosis
US5063210A (en) *	1989-04-20	1991-11-05	Lange Iii Louis G	Use of sulfated polysaccharides to decrease cholesterol and fatty acid absorption
EP0796864A2 (en) *	1992-06-26	1997-09-24	Pfizer Inc.	Steroidal glycosides for treating hypercholesterolemia
LT3300B (en) *	1992-12-23	1995-06-26	Schering Corp	Combination of a cholesterol biosynhtesis inhibitor and a beta- lactam cholesterol absorbtion inhibitor

1995
- 1995-06-07 US US08/793,802 patent/US5807834A/en not_active Expired - Fee Related
- 1995-06-07 AU AU24532/95A patent/AU2453295A/en not_active Abandoned
- 1995-06-07 JP JP8511549A patent/JPH09511753A/ja active Pending
- 1995-06-07 WO PCT/IB1995/000447 patent/WO1996009827A2/en not_active Application Discontinuation
- 1995-06-07 MX MX9702175A patent/MX9702175A/es not_active Application Discontinuation
- 1995-06-07 EP EP95918721A patent/EP0782451A1/en not_active Withdrawn
- 1995-06-07 CA CA002200436A patent/CA2200436A1/en not_active Abandoned
- 1995-09-14 IL IL11531095A patent/IL115310A0/xx unknown
- 1995-09-19 BR BR9504072A patent/BR9504072A/pt not_active Application Discontinuation
- 1995-09-19 ZA ZA957879A patent/ZA957879B/xx unknown
- 1995-09-20 HR HR08/308,908A patent/HRP950488A2/hr not_active Application Discontinuation
1997
- 1997-03-19 FI FI971151A patent/FI971151A/fi not_active Application Discontinuation

Also Published As

Publication number	Publication date
MX9702175A (es)	1997-06-28
WO1996009827A3 (en)	1996-05-23
EP0782451A1 (en)	1997-07-09
AU2453295A (en)	1996-04-19
US5807834A (en)	1998-09-15
BR9504072A (pt)	1996-07-30
JPH09511753A (ja)	1997-11-25
FI971151A0 (fi)	1997-03-19
ZA957879B (en)	1997-03-19
IL115310A0 (en)	1995-12-31
WO1996009827A2 (en)	1996-04-04
CA2200436A1 (en)	1996-04-04
FI971151A (fi)	1997-03-19

Legal Events

Date	Code	Title
1997-08-31	A1OB	Publication of a patent application
1998-02-27	AIPI	Request for the grant of a patent on the basis of a substantive examination of a patent application
2000-05-24	OBST	Application withdrawn

Publication	Publication Date	Title
HRP950488A2 (en)	1997-08-31	Combination therapy for hypercholesterolemia
RU2232155C2 (ru)	2004-07-10	Производные 1,4-бензотиазепин-1,1-диоксида, замещенные остатками сахаров, способ их получения, лекарственное средство на их основе и способ его получения
US20200383970A1 (en)	2020-12-10	Morphinan Derivatives with High Oral Bioavailability
US9457033B2 (en)	2016-10-04	Steroid alkaloids and uses thereof as antimicrobial agents against electron transport-deficient microbes and as potentiators for antimicrobial agents against pathogenic bacteria
US7012069B2 (en)	2006-03-14	Liver X receptor agonists
JP5620392B2 (ja)	2014-11-05	クロストリジウム・ディフィシレ胞子の発芽および伸長を阻害するための方法および組成物
US8957056B2 (en)	2015-02-17	Migrastatin analogs in the treatment of cancer
US8324284B2 (en)	2012-12-04	Migrastatin analogs and uses thereof
SK48398A3 (en)	1998-11-04	Sugar-substituted 2-azetidinones useful as hypocholesterolemic agents
US20230134986A1 (en)	2023-05-04	Glucose triptolide conjugates and uses thereof
IL126346A (en)	2004-06-20	Betulinic acid derivatives and pharmaceutical compositions comprising them
US5466687A (en)	1995-11-14	Arylidene-1-azacycloalkanes and arylalkyl-1-azacyclo-alkanes, their salts, medicaments containing these compounds and their use, and processes for their preparation
US20230009312A1 (en)	2023-01-12	Androstane Derivatives with Activity as Pure or Predominantly Pure Stimulators of SERCA2a for the Treatment of Heart Failure.
JP5619001B2 (ja)	2014-11-05	ストレプトスピロール誘導体
JP4781549B2 (ja)	2011-09-28	不飽和カルバ糖アミン誘導体及びそれを用いるグリコシダーゼ阻害剤
Iwasawa et al.	1996	J-104,123, a novel and orally-active inhibitor of squalene synthase: Stereoselective synthesis and cholesterol lowering effects in dogs
HRP20000377A2 (en)	2000-12-31	Novel urethanes derived from azacycloalkanes,their thio and dithio analogues, their salts, pharmaceutical preparations containing the indicated compounds and their use and preparation processes
WO2010061787A1 (ja)	2010-06-03	Ａｃａｔ２阻害活性を有するボーベリオライド
US20020193418A1 (en)	2002-12-19	Methods of using and preparing thiolutin dioxide
WO2014172776A1 (en)	2014-10-30	Compounds for the treatment of mucopolysaccharidoses
EP4161481A1 (en)	2023-04-12	Antibacterial synthetic-bioinformatic natural products and uses thereof
JP2006131595A (ja)	2006-05-25	発癌予防剤及びシクロアルタン型トリテルペン系化合物の製造方法
JPH06321782A (ja)	1994-11-22	ステロイド化合物
AU2002250997A1 (en)	2003-03-20	Use of thiolutin dioxide and its derivatives in the manufacture of a medicament for the treatment of CNS disorders and a process for the preparation thereof
JP2004196680A (ja)	2004-07-15	新規ｆｋｉ−０９２９物質およびその製造法