CN110944997A - Fxr受体激动剂 - Google Patents
Fxr受体激动剂 Download PDFInfo
- Publication number
- CN110944997A CN110944997A CN201880045263.0A CN201880045263A CN110944997A CN 110944997 A CN110944997 A CN 110944997A CN 201880045263 A CN201880045263 A CN 201880045263A CN 110944997 A CN110944997 A CN 110944997A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- membered
- group
- alkoxy
- radical
- 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.)
- Granted
Links
- 102100038495 Bile acid receptor Human genes 0.000 title abstract description 33
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 title abstract description 33
- 229940044601 receptor agonist Drugs 0.000 title description 2
- 239000000018 receptor agonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 150000002148 esters Chemical class 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 66
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 38
- 201000010099 disease Diseases 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- -1 hydroxy, amino Chemical group 0.000 claims description 282
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 84
- 125000005843 halogen group Chemical group 0.000 claims description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 61
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 55
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
- 125000005842 heteroatom Chemical group 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 125000004432 carbon atom Chemical group C* 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 229910052717 sulfur Inorganic materials 0.000 claims description 31
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 29
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- 125000002947 alkylene group Chemical group 0.000 claims description 21
- 239000000126 substance Substances 0.000 claims description 21
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 18
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 18
- 125000004069 aziridinyl group Chemical group 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 125000002393 azetidinyl group Chemical group 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 14
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 13
- 125000004122 cyclic group Chemical group 0.000 claims description 13
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 13
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 13
- 125000003566 oxetanyl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 10
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 206010008635 Cholestasis Diseases 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 231100000359 cholestasis Toxicity 0.000 claims description 10
- 230000007870 cholestasis Effects 0.000 claims description 10
- 208000006454 hepatitis Diseases 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 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 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 7
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 231100000283 hepatitis Toxicity 0.000 claims description 7
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 7
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 7
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 6
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 6
- 206010016654 Fibrosis Diseases 0.000 claims description 6
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 6
- 208000010706 fatty liver disease Diseases 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 5
- 230000003463 hyperproliferative effect Effects 0.000 claims description 5
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 4
- 125000006721 (C5-C10) heteroaryl (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 claims description 4
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 4
- 208000026594 alcoholic fatty liver disease Diseases 0.000 claims description 4
- 239000003613 bile acid Substances 0.000 claims description 4
- 201000001883 cholelithiasis Diseases 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 4
- 230000002440 hepatic effect Effects 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 4
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008909 Chronic Hepatitis Diseases 0.000 claims description 3
- 206010048832 Colon adenoma Diseases 0.000 claims description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 208000004930 Fatty Liver Diseases 0.000 claims description 3
- 206010016262 Fatty liver alcoholic Diseases 0.000 claims description 3
- 206010019663 Hepatic failure Diseases 0.000 claims description 3
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 3
- 206010019799 Hepatitis viral Diseases 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 201000002150 Progressive familial intrahepatic cholestasis Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 230000001587 cholestatic effect Effects 0.000 claims description 3
- 230000007882 cirrhosis Effects 0.000 claims description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
- 201000010897 colon adenocarcinoma Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 3
- 208000001024 intrahepatic cholestasis Diseases 0.000 claims description 3
- 230000007872 intrahepatic cholestasis Effects 0.000 claims description 3
- 231100000835 liver failure Toxicity 0.000 claims description 3
- 208000007903 liver failure Diseases 0.000 claims description 3
- 230000007774 longterm Effects 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 230000001613 neoplastic effect Effects 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 208000015768 polyposis Diseases 0.000 claims description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 201000001862 viral hepatitis Diseases 0.000 claims description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 206010023138 Jaundice neonatal Diseases 0.000 claims description 2
- 201000006346 Neonatal Jaundice Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 235000016709 nutrition Nutrition 0.000 claims description 2
- 230000035764 nutrition Effects 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 206010023126 Jaundice Diseases 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 89
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 201
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 86
- 210000004027 cell Anatomy 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 71
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- 150000003254 radicals Chemical class 0.000 description 68
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- 239000000047 product Substances 0.000 description 38
- 239000000243 solution Substances 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
- 238000010898 silica gel chromatography Methods 0.000 description 33
- 238000001179 sorption measurement Methods 0.000 description 33
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 29
- 239000012074 organic phase Substances 0.000 description 29
- 239000000523 sample Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 26
- DMPZJACLHDWUFS-UHFFFAOYSA-N 1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CSC2=C1 DMPZJACLHDWUFS-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000010839 reverse transcription Methods 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 238000002474 experimental method Methods 0.000 description 18
- 239000002299 complementary DNA Substances 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 102000001479 Member 11 Subfamily B ATP Binding Cassette Transporter Human genes 0.000 description 15
- 108010093662 Member 11 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 15
- 238000011529 RT qPCR Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 238000000605 extraction Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 125000005605 benzo group Chemical group 0.000 description 12
- 210000004185 liver Anatomy 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- 239000012224 working solution Substances 0.000 description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 11
- 238000004113 cell culture Methods 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 125000006413 ring segment Chemical group 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 108010019160 Pancreatin Proteins 0.000 description 9
- 230000001270 agonistic effect Effects 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 238000011534 incubation Methods 0.000 description 9
- 239000006166 lysate Substances 0.000 description 9
- 108020004999 messenger RNA Proteins 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- 229940055695 pancreatin Drugs 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- KUGVOFOZBFALKT-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CC2CC1CC2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 Chemical compound CC(C)(C)OC(=O)N1CC2CC1CC2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 KUGVOFOZBFALKT-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 239000001963 growth medium Substances 0.000 description 7
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- MDFXZDUEXDDCOP-UHFFFAOYSA-N 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole Chemical compound ClCC1=C(C2CC2)ON=C1C1=C(Cl)C=CC=C1Cl MDFXZDUEXDDCOP-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 239000013592 cell lysate Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 6
- 230000002503 metabolic effect Effects 0.000 description 6
- XYBYYJDNPLGJSA-UHFFFAOYSA-N methyl 2-bromo-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)C1=CC=C2N=C(Br)SC2=C1 XYBYYJDNPLGJSA-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 6
- KZSKGLFYQAYZCO-UHFFFAOYSA-N 2-[3-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]-3-hydroxyazetidin-1-yl]pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(N2CC(O)(C2)C=2C(=CC(OCC=3C(=NOC=3C3CC3)C=3C(=CC=CC=3Cl)Cl)=CC=2)Cl)=C1 KZSKGLFYQAYZCO-UHFFFAOYSA-N 0.000 description 5
- 229940122206 Farnesoid X receptor antagonist Drugs 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000013614 RNA sample Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000001853 liver microsome Anatomy 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- PABFVGKPNHVSCG-UHFFFAOYSA-N tert-butyl 5-hydroxy-3-azabicyclo[2.2.1]heptane-3-carboxylate Chemical compound C1C(O)C2N(C(=O)OC(C)(C)C)CC1C2 PABFVGKPNHVSCG-UHFFFAOYSA-N 0.000 description 5
- 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 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 230000001143 conditioned effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZQJRMBVCFPZYDV-UHFFFAOYSA-N tert-butyl 6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)COC1CC2CN(C1C2)C(=O)OC(C)(C)C ZQJRMBVCFPZYDV-UHFFFAOYSA-N 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
- 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
- 238000003260 vortexing Methods 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- HDPGSWMTDGGUEB-XHNCKOQMSA-N C1[C@@H]2N(C(=O)OC(C)(C)C)C[C@H]1[C@H](O)C2 Chemical compound C1[C@@H]2N(C(=O)OC(C)(C)C)C[C@H]1[C@H](O)C2 HDPGSWMTDGGUEB-XHNCKOQMSA-N 0.000 description 3
- 241000282465 Canis Species 0.000 description 3
- VSJRURNHBNKEKX-UHFFFAOYSA-N Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CC2CC1CN2 Chemical compound Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CC2CC1CN2 VSJRURNHBNKEKX-UHFFFAOYSA-N 0.000 description 3
- 102100038637 Cytochrome P450 7A1 Human genes 0.000 description 3
- 241000283073 Equus caballus Species 0.000 description 3
- 241000282324 Felis Species 0.000 description 3
- 101000957672 Homo sapiens Cytochrome P450 7A1 Proteins 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 102000007330 LDL Lipoproteins Human genes 0.000 description 3
- 108010007622 LDL Lipoproteins Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- 238000002123 RNA extraction Methods 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000006037 cell lysis Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 235000019416 cholic acid Nutrition 0.000 description 3
- 125000006165 cyclic alkyl group Chemical group 0.000 description 3
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 108020001756 ligand binding domains Proteins 0.000 description 3
- 210000001589 microsome Anatomy 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- HDPGSWMTDGGUEB-UHFFFAOYSA-N tert-butyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1C(O)C2 HDPGSWMTDGGUEB-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- ZMULZVILNURIQY-LFYBBSHMSA-N (ne)-n-[[2-(trifluoromethoxy)phenyl]methylidene]hydroxylamine Chemical compound O\N=C\C1=CC=CC=C1OC(F)(F)F ZMULZVILNURIQY-LFYBBSHMSA-N 0.000 description 2
- DEZDVAAAZZONAM-UHFFFAOYSA-N 4-(bromomethyl)-5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole Chemical compound FC(F)(F)OC1=CC=CC=C1C1=NOC(C2CC2)=C1CBr DEZDVAAAZZONAM-UHFFFAOYSA-N 0.000 description 2
- BCIMCTBZUZCJSK-BMMKQCRMSA-N 4-[[(1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-yl]oxymethyl]-5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole 2,2,2-trifluoroacetic acid Chemical compound C1CC1C2=C(C(=NO2)C3=CC=CC=C3OC(F)(F)F)CO[C@@H]4C[C@@H]5C[C@H]4CN5.C(=O)(C(F)(F)F)O BCIMCTBZUZCJSK-BMMKQCRMSA-N 0.000 description 2
- JSKXHTHMCCDEGD-UHFFFAOYSA-M 4-amino-3-fluorobenzoate Chemical compound NC1=CC=C(C([O-])=O)C=C1F JSKXHTHMCCDEGD-UHFFFAOYSA-M 0.000 description 2
- KPFWYFYRULFDQP-UHFFFAOYSA-N 5-azabicyclo[2.2.1]hept-2-ene Chemical compound C1C2CNC1C=C2 KPFWYFYRULFDQP-UHFFFAOYSA-N 0.000 description 2
- 241000415078 Anemone hepatica Species 0.000 description 2
- KUGVOFOZBFALKT-YZVOILCLSA-N CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 Chemical compound CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 KUGVOFOZBFALKT-YZVOILCLSA-N 0.000 description 2
- VITVWFGLUTXYIT-TWOQFEAHSA-N CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1ccccc1OC(F)(F)F)C1CC1 Chemical compound CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1ccccc1OC(F)(F)F)C1CC1 VITVWFGLUTXYIT-TWOQFEAHSA-N 0.000 description 2
- KUGVOFOZBFALKT-CLCXKQKWSA-N CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1C[C@@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 Chemical compound CC(C)(C)OC(=O)N1C[C@H]2C[C@@H]1C[C@@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 KUGVOFOZBFALKT-CLCXKQKWSA-N 0.000 description 2
- BSJNTJUMSCVTFV-UHFFFAOYSA-N Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CC2CNC1C2 Chemical compound Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CC2CNC1C2 BSJNTJUMSCVTFV-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 229940126656 GS-4224 Drugs 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102000034527 Retinoid X Receptors Human genes 0.000 description 2
- 108010038912 Retinoid X Receptors Proteins 0.000 description 2
- YJPRZVHHSVCUIU-UHFFFAOYSA-N [5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanol Chemical compound OCC1=C(C2CC2)ON=C1C1=CC=CC=C1OC(F)(F)F YJPRZVHHSVCUIU-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 108091092328 cellular RNA Proteins 0.000 description 2
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 2
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 2
- 239000002812 cholic acid derivative Substances 0.000 description 2
- 150000001842 cholic acids Chemical class 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid 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](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid 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](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- SYZNSAWWLCRFFT-UHFFFAOYSA-N methyl 2-amino-4-methoxy-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2N=C(N)SC2=C1 SYZNSAWWLCRFFT-UHFFFAOYSA-N 0.000 description 2
- SGWVZBCLQAXEJM-UHFFFAOYSA-N methyl 2-bromo-4-fluoro-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)C1=CC(F)=C2N=C(Br)SC2=C1 SGWVZBCLQAXEJM-UHFFFAOYSA-N 0.000 description 2
- YVEDWWBAPREOBF-UHFFFAOYSA-N methyl 2-bromo-4-methoxy-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2N=C(Br)SC2=C1 YVEDWWBAPREOBF-UHFFFAOYSA-N 0.000 description 2
- FKMZNQQOPCCUTD-UHFFFAOYSA-N methyl 3-fluoro-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(F)=C1 FKMZNQQOPCCUTD-UHFFFAOYSA-N 0.000 description 2
- DOMJYWCXCVFKCA-UHFFFAOYSA-N methyl 4-amino-3-fluorobenzoate Chemical compound COC(=O)C1=CC=C(N)C(F)=C1 DOMJYWCXCVFKCA-UHFFFAOYSA-N 0.000 description 2
- INMVEWNAYCVPAI-UHFFFAOYSA-N methyl 5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole-4-carboxylate Chemical compound COC(=O)C1=C(C2CC2)ON=C1C1=CC=CC=C1OC(F)(F)F INMVEWNAYCVPAI-UHFFFAOYSA-N 0.000 description 2
- 230000003228 microsomal effect Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 102000006255 nuclear receptors Human genes 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 2
- 229960001601 obeticholic acid Drugs 0.000 description 2
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 108010068815 steroid hormone 7-alpha-hydroxylase Proteins 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- HDPGSWMTDGGUEB-HLTSFMKQSA-N tert-butyl (1r,4r,5s)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1[C@H]2N(C(=O)OC(C)(C)C)C[C@@H]1[C@@H](O)C2 HDPGSWMTDGGUEB-HLTSFMKQSA-N 0.000 description 2
- ZATXHTCUZAWODK-DTWKUNHWSA-N tert-butyl (1r,4s)-5-azabicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)[C@]2([H])C=C[C@@]1([H])C2 ZATXHTCUZAWODK-DTWKUNHWSA-N 0.000 description 2
- LODUSBSRDZAOFQ-UHFFFAOYSA-N tert-butyl 6-(4-nitrobenzoyl)oxy-2-azabicyclo[2.2.1]heptane-2-carboxylate Chemical compound [N+](=O)([O-])C1=CC=C(C(=O)OC2CC3CN(C2C3)C(=O)OC(C)(C)C)C=C1 LODUSBSRDZAOFQ-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- DDUFYKNOXPZZIW-UHNVWZDZSA-N (1s,4r)-3-azabicyclo[2.2.1]hept-5-en-2-one Chemical compound C1[C@@H]2C(=O)N[C@H]1C=C2 DDUFYKNOXPZZIW-UHNVWZDZSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CPHXLFKIUVVIOQ-UHFFFAOYSA-N 2-(trifluoromethoxy)benzaldehyde Chemical compound FC(F)(F)OC1=CC=CC=C1C=O CPHXLFKIUVVIOQ-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- HTTUWXPQGHCWCO-UHFFFAOYSA-N 3-azabicyclo[2.2.1]heptan-5-ol;hydrochloride Chemical compound Cl.C1NC2C(O)CC1C2 HTTUWXPQGHCWCO-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- PNZIYSWKRBYITO-UHFFFAOYSA-N 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole Chemical compound ClC1=CC=CC(Cl)=C1C1=NOC(C2CC2)=C1CBr PNZIYSWKRBYITO-UHFFFAOYSA-N 0.000 description 1
- VSJRURNHBNKEKX-HSMVNMDESA-N 4-[[(1R,4R,5S)-2-azabicyclo[2.2.1]heptan-5-yl]oxymethyl]-5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole Chemical compound Clc1cccc(Cl)c1-c1noc(C2CC2)c1CO[C@H]1C[C@H]2C[C@@H]1CN2 VSJRURNHBNKEKX-HSMVNMDESA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- TWSIYGATPWEKBK-UHFFFAOYSA-N 4h-1,3-benzodioxine Chemical compound C1=CC=C2OCOCC2=C1 TWSIYGATPWEKBK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101150048692 ABCB11 gene Proteins 0.000 description 1
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 101150075266 CYP7A1 gene Proteins 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 1
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- UDSFAEKRVUSQDD-UHFFFAOYSA-N Dimethyl adipate Chemical compound COC(=O)CCCCC(=O)OC UDSFAEKRVUSQDD-UHFFFAOYSA-N 0.000 description 1
- 101710150311 Dolichyl-phosphooligosaccharide-protein glycotransferase Proteins 0.000 description 1
- 101710202156 Dolichyl-phosphooligosaccharide-protein glycotransferase 1 Proteins 0.000 description 1
- 101710202150 Dolichyl-phosphooligosaccharide-protein glycotransferase 2 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- NEYSUOWNUVQOBV-UHFFFAOYSA-N FC(C(=O)O)(F)F.C12NCC(C(C1)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C2 Chemical compound FC(C(=O)O)(F)F.C12NCC(C(C1)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C2 NEYSUOWNUVQOBV-UHFFFAOYSA-N 0.000 description 1
- NEYSUOWNUVQOBV-CUAOWDJTSA-N FC(C(=O)O)(F)F.[C@@H]12NC[C@@H]([C@@H](C1)OCC=1C(=NOC1C1CC1)C1=C(C=CC=C1Cl)Cl)C2 Chemical compound FC(C(=O)O)(F)F.[C@@H]12NC[C@@H]([C@@H](C1)OCC=1C(=NOC1C1CC1)C1=C(C=CC=C1Cl)Cl)C2 NEYSUOWNUVQOBV-CUAOWDJTSA-N 0.000 description 1
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102100021383 Guanine nucleotide exchange factor DBS Human genes 0.000 description 1
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100023172 Nuclear receptor subfamily 0 group B member 2 Human genes 0.000 description 1
- VYLOOGHLKSNNEK-PIIMJCKOSA-N OC(=O)c1cc(F)c2nc(sc2c1)N1[C@H]2CC[C@@H]1C[C@@H](C2)OCc1c(onc1-c1ccccc1OC(F)(F)F)C1CC1 Chemical compound OC(=O)c1cc(F)c2nc(sc2c1)N1[C@H]2CC[C@@H]1C[C@@H](C2)OCc1c(onc1-c1ccccc1OC(F)(F)F)C1CC1 VYLOOGHLKSNNEK-PIIMJCKOSA-N 0.000 description 1
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 1
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 231100000836 acute liver failure Toxicity 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 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
- 238000007405 data analysis Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 238000010832 independent-sample T-test Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 208000006663 kernicterus Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000010150 least significant difference test Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 108010003814 member 2 group B nuclear receptor subfamily 0 Proteins 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- UNJLICBWHHMOFV-UHFFFAOYSA-N methyl 2-amino-4-fluoro-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)C1=CC(F)=C2N=C(N)SC2=C1 UNJLICBWHHMOFV-UHFFFAOYSA-N 0.000 description 1
- UCCRMZWBOIVMKI-UHFFFAOYSA-N methyl 2-amino-4-methyl-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)C1=CC(C)=C2N=C(N)SC2=C1 UCCRMZWBOIVMKI-UHFFFAOYSA-N 0.000 description 1
- XSEAGAYSAHNOQI-UHFFFAOYSA-N methyl 2-bromo-4-methyl-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)C1=CC(C)=C2N=C(Br)SC2=C1 XSEAGAYSAHNOQI-UHFFFAOYSA-N 0.000 description 1
- RIJWDPRXCXJDPK-UHFFFAOYSA-N methyl 3-cyclopropyl-3-oxopropanoate Chemical compound COC(=O)CC(=O)C1CC1 RIJWDPRXCXJDPK-UHFFFAOYSA-N 0.000 description 1
- DJLFOMMCQBAMAA-UHFFFAOYSA-N methyl 4-amino-3-methoxybenzoate Chemical compound COC(=O)C1=CC=C(N)C(OC)=C1 DJLFOMMCQBAMAA-UHFFFAOYSA-N 0.000 description 1
- ZHIPSMIKSRYZFV-UHFFFAOYSA-N methyl 4-amino-3-methylbenzoate Chemical compound COC(=O)C1=CC=C(N)C(C)=C1 ZHIPSMIKSRYZFV-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- LCZKSSFWTSEFBD-UHFFFAOYSA-N n-hydroxy-2-(trifluoromethoxy)benzenecarboximidoyl chloride Chemical compound ON=C(Cl)C1=CC=CC=C1OC(F)(F)F LCZKSSFWTSEFBD-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 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
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 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
- 230000019491 signal transduction Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- ZATXHTCUZAWODK-UHFFFAOYSA-N tert-butyl 5-azabicyclo[2.2.1]hept-2-ene-5-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1C=C2 ZATXHTCUZAWODK-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
- 239000012085 test solution Substances 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- DDUFYKNOXPZZIW-CRCLSJGQSA-N vince lactam Chemical compound C1[C@H]2C(=O)N[C@@H]1C=C2 DDUFYKNOXPZZIW-CRCLSJGQSA-N 0.000 description 1
Classifications
-
- 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P3/08—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
- A61P35/00—Antineoplastic agents
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明属于医药技术领域，具体涉及式(I)所示的化合物、其药学上可接受的盐、其酯或它们的立体异构体，其中，R1、X1、X2、M、Ar、环A、环B、L如说明书中所定义；本发明还涉及所述化合物、其药学上可接受的盐、其酯或它们的立体异构体的制备方法、含有所述化合物、其药学上可接受的盐、其酯或它们的立体异构体的药物组合物和药物制剂，及所述化合物、其药学上可接受的盐、其酯或它们的立体异构体在用于制备治疗和/或预防由FXR受体介导的疾病的药物中的应用。
Description
PCT国内申请，说明书已公开。
Claims (16)
- PCT国内申请，权利要求书已公开。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110081028.2A CN112876467B (zh) | 2017-07-06 | 2018-07-06 | Fxr受体激动剂 |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710547157X | 2017-07-06 | ||
| CN201710547157 | 2017-07-06 | ||
| PCT/CN2018/094813 WO2019007418A1 (zh) | 2017-07-06 | 2018-07-06 | Fxr受体激动剂 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110081028.2A Division CN112876467B (zh) | 2017-07-06 | 2018-07-06 | Fxr受体激动剂 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110944997A true CN110944997A (zh) | 2020-03-31 |
| CN110944997B CN110944997B (zh) | 2021-04-09 |
Family
ID=64950610
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880045263.0A Active CN110944997B (zh) | 2017-07-06 | 2018-07-06 | Fxr受体激动剂 |
| CN202110081028.2A Active CN112876467B (zh) | 2017-07-06 | 2018-07-06 | Fxr受体激动剂 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110081028.2A Active CN112876467B (zh) | 2017-07-06 | 2018-07-06 | Fxr受体激动剂 |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US11352358B2 (zh) |
| EP (1) | EP3650449B1 (zh) |
| JP (1) | JP6997870B2 (zh) |
| KR (1) | KR102400183B1 (zh) |
| CN (2) | CN110944997B (zh) |
| AU (1) | AU2018298253B2 (zh) |
| BR (1) | BR112020000180A2 (zh) |
| CA (1) | CA3068928C (zh) |
| MX (1) | MX2020000268A (zh) |
| WO (1) | WO2019007418A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110177783A (zh) * | 2016-08-23 | 2019-08-27 | 阿德利克斯股份有限公司 | 用于治疗代谢病状和病症的激素受体调节剂 |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2981503C (en) | 2015-03-31 | 2023-09-19 | Enanta Pharmaceuticals, Inc. | Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof |
| WO2018039384A1 (en) | 2016-08-23 | 2018-03-01 | Ardelyx, Inc. | Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as fxr activators |
| KR20190056436A (ko) | 2016-10-04 | 2019-05-24 | 이난타 파마슈티칼스, 인코포레이티드 | Fxr 작용제로서의 이속사졸 유사체 및 그의 사용 방법 |
| US10597391B2 (en) | 2016-10-26 | 2020-03-24 | Enanta Pharmaceuticals, Inc. | Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof |
| EP3681881B1 (en) | 2017-09-14 | 2022-11-02 | Ardelyx, Inc. | Hormone receptor modulators for treating metabolic mutagenic and fibrotic conditions and disorders |
| WO2019118571A1 (en) | 2017-12-12 | 2019-06-20 | Enanta Pharmaceuticals, Inc. | Isoxazole analogs as fxr agonists and methods of use thereof |
| CN110128432B (zh) | 2018-02-02 | 2021-03-02 | 广东东阳光药业有限公司 | 含氮三环化合物及其在药物中的应用 |
| WO2019160813A1 (en) | 2018-02-14 | 2019-08-22 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as fxr agonists and methods of use thereof |
| US11555032B2 (en) | 2019-05-13 | 2023-01-17 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as FXR agonists and methods of use thereof |
| AU2020312735A1 (en) | 2019-07-18 | 2021-12-16 | Enyo Pharma | Method for decreasing adverse-effects of interferon |
| WO2021014349A1 (en) | 2019-07-23 | 2021-01-28 | Novartis Ag | Treatment comprising fxr agonists |
| CN114126657A (zh) | 2019-07-23 | 2022-03-01 | 诺华股份有限公司 | 使用fxr激动剂的肝脏疾病的组合治疗 |
| JP2022547452A (ja) | 2019-09-03 | 2022-11-14 | ノバルティス アーゲー | Ａｃｔｒｉｉ受容体拮抗薬を含む肝疾患または肝臓障害の治療 |
| CN114401745A (zh) | 2019-09-19 | 2022-04-26 | 诺华股份有限公司 | 包含fxr激动剂的治疗 |
| CN114502198A (zh) | 2019-09-30 | 2022-05-13 | 诺华股份有限公司 | 包括使用fxr激动剂的治疗 |
| TW202135811A (zh) | 2019-12-20 | 2021-10-01 | 瑞士商諾華公司 | 使用整聯蛋白抑制劑組合治療肝臟疾病 |
| AU2021207253A1 (en) | 2020-01-15 | 2022-06-09 | Centre National De La Recherche Scientifique | Use of FXR agonists for treating an infection by hepatitis D virus |
| WO2022101853A1 (en) | 2020-11-16 | 2022-05-19 | Novartis Ag | Method of determining liver fibrosis |
| WO2022152770A1 (en) | 2021-01-14 | 2022-07-21 | Enyo Pharma | Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection |
| WO2022179636A1 (zh) * | 2021-02-27 | 2022-09-01 | 轩竹生物科技股份有限公司 | Fxr受体激动剂的晶型 |
| WO2022229302A1 (en) | 2021-04-28 | 2022-11-03 | Enyo Pharma | Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103443099A (zh) * | 2010-12-20 | 2013-12-11 | Irm责任有限公司 | 调节fxr的组合物和方法 |
| WO2016096115A1 (en) * | 2014-12-17 | 2016-06-23 | Gilead Sciences, Inc. | Hydroxy containing fxr (nr1h4) modulating compounds |
| WO2016097933A1 (en) * | 2014-12-18 | 2016-06-23 | Novartis Ag | Azabicyclooctane derivatives as fxr agonists for use in the treatment of liver and gastrointestinal diseases |
| WO2018039386A1 (en) * | 2016-08-23 | 2018-03-01 | Ardelyx, Inc. | Hormone receptor modulators for treating metabolic conditions and disorders |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69940958D1 (de) | 1998-12-23 | 2009-07-16 | Glaxo Group Ltd | Bestimmungsmethode fur liganden der nuklearen rezeptoren |
| EP2289883A1 (en) | 2009-08-19 | 2011-03-02 | Phenex Pharmaceuticals AG | Novel FXR (NR1H4) binding and activity modulating compounds |
| US20130261108A1 (en) * | 2010-12-20 | 2013-10-03 | Irm Llc | Compositions and methods for modulating farnesoid x receptors |
-
2018
- 2018-07-06 MX MX2020000268A patent/MX2020000268A/es unknown
- 2018-07-06 CN CN201880045263.0A patent/CN110944997B/zh active Active
- 2018-07-06 BR BR112020000180-5A patent/BR112020000180A2/pt unknown
- 2018-07-06 CA CA3068928A patent/CA3068928C/en active Active
- 2018-07-06 EP EP18829134.8A patent/EP3650449B1/en active Active
- 2018-07-06 US US16/628,169 patent/US11352358B2/en active Active
- 2018-07-06 AU AU2018298253A patent/AU2018298253B2/en active Active
- 2018-07-06 JP JP2020522777A patent/JP6997870B2/ja active Active
- 2018-07-06 WO PCT/CN2018/094813 patent/WO2019007418A1/zh unknown
- 2018-07-06 KR KR1020207003502A patent/KR102400183B1/ko active IP Right Grant
- 2018-07-06 CN CN202110081028.2A patent/CN112876467B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103443099A (zh) * | 2010-12-20 | 2013-12-11 | Irm责任有限公司 | 调节fxr的组合物和方法 |
| WO2016096115A1 (en) * | 2014-12-17 | 2016-06-23 | Gilead Sciences, Inc. | Hydroxy containing fxr (nr1h4) modulating compounds |
| WO2016097933A1 (en) * | 2014-12-18 | 2016-06-23 | Novartis Ag | Azabicyclooctane derivatives as fxr agonists for use in the treatment of liver and gastrointestinal diseases |
| WO2018039386A1 (en) * | 2016-08-23 | 2018-03-01 | Ardelyx, Inc. | Hormone receptor modulators for treating metabolic conditions and disorders |
| CN110177783A (zh) * | 2016-08-23 | 2019-08-27 | 阿德利克斯股份有限公司 | 用于治疗代谢病状和病症的激素受体调节剂 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110177783A (zh) * | 2016-08-23 | 2019-08-27 | 阿德利克斯股份有限公司 | 用于治疗代谢病状和病症的激素受体调节剂 |
| CN110177783B (zh) * | 2016-08-23 | 2023-06-06 | 阿德利克斯股份有限公司 | 用于治疗代谢病状和病症的激素受体调节剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3650449A4 (en) | 2021-04-07 |
| AU2018298253B2 (en) | 2020-11-19 |
| AU2018298253A1 (en) | 2020-02-27 |
| CN110944997B (zh) | 2021-04-09 |
| JP6997870B2 (ja) | 2022-02-10 |
| EP3650449A1 (en) | 2020-05-13 |
| EP3650449B1 (en) | 2023-08-23 |
| BR112020000180A2 (pt) | 2020-07-14 |
| US11352358B2 (en) | 2022-06-07 |
| CA3068928A1 (en) | 2019-01-10 |
| JP2020527598A (ja) | 2020-09-10 |
| WO2019007418A1 (zh) | 2019-01-10 |
| CN112876467A (zh) | 2021-06-01 |
| US20210024522A1 (en) | 2021-01-28 |
| CA3068928C (en) | 2022-05-31 |
| MX2020000268A (es) | 2020-07-22 |
| KR102400183B1 (ko) | 2022-05-18 |
| KR20200029509A (ko) | 2020-03-18 |
| CN112876467B (zh) | 2023-06-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110944997B (zh) | Fxr受体激动剂 | |
| CN108602811B (zh) | Fxr受体激动剂 | |
| CN111868056B (zh) | 1,2,4-噁二唑类化合物及其制备方法和医药用途 | |
| CN112955448B (zh) | 芳环或芳杂环类化合物及其制备方法和医药用途 | |
| CN107021957A (zh) | Fxr受体激动剂 | |
| JPWO2011052756A1 (ja) | 新規３−ヒドロキシ−５−アリールイソキサゾール誘導体 | |
| CN109320517B (zh) | Fxr受体激动剂 | |
| CN112334467B (zh) | Fxr受体激动剂 | |
| CN109320509B (zh) | Fxr受体激动剂 | |
| WO2019104748A1 (zh) | 化合物在制备药物中的用途 | |
| CN109575008B (zh) | Fxr受体激动剂 | |
| CN109265471B (zh) | Fxr受体激动剂 | |
| CN110563720B (zh) | 磺酰胺类化合物及其制备方法和医药用途 | |
| CN111763173B (zh) | 苯乙基咪唑类衍生物及其用途 | |
| WO2023143402A1 (zh) | 甾类化合物、其制备方法和应用 | |
| CN108610285B (zh) | 苯乙酮类化合物、其制备方法及其在防治脂肪肝方面的应用 | |
| CN116925059A (zh) | 一类新型异恶唑类fxr激动剂、其制备方法及其作为药物的用途 | |
| JPS59204188A (ja) | ラクトン誘導体 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40016529 Country of ref document: HK |
|
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor Applicant after: Xuanzhu (Shijiazhuang) Biotechnology Co.,Ltd. Address before: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor Applicant before: Xuanzhu (Hainan) Pharmaceutical Technology Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province 203c507 Applicant after: Xuanzhu Biotechnology Co.,Ltd. Address before: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province 203c507 Applicant before: Xuanzhu (Shijiazhuang) Biotechnology Co.,Ltd. Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province 203c507 Applicant after: Xuanzhu (Shijiazhuang) Biotechnology Co.,Ltd. Address before: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor Applicant before: Xuanzhu (Hainan) Pharmaceutical Technology Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province Patentee after: Xuanzhu Biotechnology Co.,Ltd. Address before: 050000 Beijing Tianjin Hebei Collaborative Innovation Demonstration Park 203c507, 769 Taihang street, high tech Zone, Shijiazhuang City, Hebei Province Patentee before: Xuanzhu Biotechnology Co.,Ltd. |