IL298144A - Combination treatment of liver disorders - Google Patents
Combination treatment of liver disordersInfo
- Publication number
- IL298144A IL298144A IL298144A IL29814422A IL298144A IL 298144 A IL298144 A IL 298144A IL 298144 A IL298144 A IL 298144A IL 29814422 A IL29814422 A IL 29814422A IL 298144 A IL298144 A IL 298144A
- Authority
- IL
- Israel
- Prior art keywords
- agonist
- compound
- patient
- fxr
- thr
- Prior art date
Links
- 238000011282 treatment Methods 0.000 title claims description 94
- 208000019423 liver disease Diseases 0.000 title claims description 62
- 150000001875 compounds Chemical class 0.000 claims description 290
- 238000000034 method Methods 0.000 claims description 207
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 196
- 150000003839 salts Chemical class 0.000 claims description 159
- 239000000556 agonist Substances 0.000 claims description 147
- 102100033451 Thyroid hormone receptor beta Human genes 0.000 claims description 142
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 137
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 claims description 134
- 108090000623 proteins and genes Proteins 0.000 claims description 93
- 230000014509 gene expression Effects 0.000 claims description 75
- 230000004761 fibrosis Effects 0.000 claims description 70
- 206010016654 Fibrosis Diseases 0.000 claims description 66
- 230000007863 steatosis Effects 0.000 claims description 66
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 66
- 210000000265 leukocyte Anatomy 0.000 claims description 59
- 238000009097 single-agent therapy Methods 0.000 claims description 57
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 56
- 210000004185 liver Anatomy 0.000 claims description 55
- 230000004054 inflammatory process Effects 0.000 claims description 52
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 50
- -1 benzoisothiazolyl Chemical group 0.000 claims description 49
- 206010061218 Inflammation Diseases 0.000 claims description 47
- 125000005843 halogen group Chemical group 0.000 claims description 42
- 208000006454 hepatitis Diseases 0.000 claims description 40
- 208000018191 liver inflammation Diseases 0.000 claims description 40
- 201000010099 disease Diseases 0.000 claims description 39
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 37
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 37
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical group 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 claims description 33
- 229960001601 obeticholic acid Drugs 0.000 claims description 33
- 208000003251 Pruritus Diseases 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 27
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 24
- 230000001476 alcoholic effect Effects 0.000 claims description 23
- 230000004913 activation Effects 0.000 claims description 19
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- XLGQSYUNOIJBNR-UHFFFAOYSA-N vonafexor Chemical compound C=1C=C2OC(C(=O)O)=CC2=C(Cl)C=1N(CC1)CCN1S(=O)(=O)C1=C(Cl)C=CC=C1Cl XLGQSYUNOIJBNR-UHFFFAOYSA-N 0.000 claims description 16
- 229940126047 MET409 Drugs 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 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 claims description 12
- 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 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229940070042 cilofexor Drugs 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 230000002440 hepatic effect Effects 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 229940070126 tropifexor Drugs 0.000 claims description 12
- 101150083327 CCR2 gene Proteins 0.000 claims description 10
- 108010035532 Collagen Proteins 0.000 claims description 10
- 102000008186 Collagen Human genes 0.000 claims description 10
- 101150106169 LGALS3 gene Proteins 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical group N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 claims description 10
- 108010028554 LDL Cholesterol Proteins 0.000 claims description 9
- 101150106019 Mmp2 gene Proteins 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 101100273740 Mus musculus Cd68 gene Proteins 0.000 claims description 8
- QNAZTOHXCZPOSA-UHFFFAOYSA-N Sobetirome Chemical compound C1=C(O)C(C(C)C)=CC(CC=2C(=CC(OCC(O)=O)=CC=2C)C)=C1 QNAZTOHXCZPOSA-UHFFFAOYSA-N 0.000 claims description 8
- 229920001436 collagen Polymers 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 8
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 8
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims description 8
- 229950007873 sobetirome Drugs 0.000 claims description 8
- 229940073650 vonafexor Drugs 0.000 claims description 8
- SJKLCUGQVVYDCX-HRNVLBFRSA-N 1-(4-tert-butylphenyl)sulfonyl-3-[(3R)-3-[(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]butyl]urea Chemical compound CC[C@H]1[C@@H](O)[C@H]2[C@@H]3CC[C@H]([C@H](C)CCNC(=O)NS(=O)(=O)c4ccc(cc4)C(C)(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)CC[C@@H](O)C[C@@H]12 SJKLCUGQVVYDCX-HRNVLBFRSA-N 0.000 claims description 7
- VPCSYAVXDAUHLT-UHFFFAOYSA-N 3-[3,5-dibromo-4-(4-hydroxy-3-propan-2-ylphenoxy)anilino]-3-oxopropanoic acid Chemical compound C1=C(O)C(C(C)C)=CC(OC=2C(=CC(NC(=O)CC(O)=O)=CC=2Br)Br)=C1 VPCSYAVXDAUHLT-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 229950011248 eprotirome Drugs 0.000 claims description 7
- 230000001965 increasing effect Effects 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 7
- 229960001225 rifampicin Drugs 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 230000001387 anti-histamine Effects 0.000 claims description 4
- 239000000739 antihistaminic agent Substances 0.000 claims description 4
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 4
- 230000001861 immunosuppressant effect Effects 0.000 claims description 4
- 239000003018 immunosuppressive agent Substances 0.000 claims description 4
- 239000003401 opiate antagonist Substances 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 claims description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 210000002744 extracellular matrix Anatomy 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 101000802091 Homo sapiens Thyroid hormone-inducible hepatic protein Proteins 0.000 claims 5
- 102100034700 Thyroid hormone-inducible hepatic protein Human genes 0.000 claims 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 101000712600 Homo sapiens Thyroid hormone receptor beta Proteins 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 210000002950 fibroblast Anatomy 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 description 158
- 108091008762 thyroid hormone receptors ß Proteins 0.000 description 141
- 241001514645 Agonis Species 0.000 description 138
- 229940125904 compound 1 Drugs 0.000 description 128
- 229940125782 compound 2 Drugs 0.000 description 58
- 241000699670 Mus sp. Species 0.000 description 54
- 239000000203 mixture Substances 0.000 description 53
- 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 45
- 230000007423 decrease Effects 0.000 description 43
- 206010012335 Dependence Diseases 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 34
- 210000002966 serum Anatomy 0.000 description 33
- 230000031018 biological processes and functions Effects 0.000 description 31
- 230000000694 effects Effects 0.000 description 30
- 239000003981 vehicle Substances 0.000 description 29
- 241000282414 Homo sapiens Species 0.000 description 24
- 241000700159 Rattus Species 0.000 description 24
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 23
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 21
- 150000003626 triacylglycerols Chemical class 0.000 description 21
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 20
- 108010082126 Alanine transaminase Proteins 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 18
- 150000002431 hydrogen Chemical group 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 17
- 230000004060 metabolic process Effects 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 238000011284 combination treatment Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 230000037361 pathway Effects 0.000 description 15
- 238000003559 RNA-seq method Methods 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 13
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 239000012535 impurity Substances 0.000 description 13
- 230000009467 reduction Effects 0.000 description 13
- 208000004930 Fatty Liver Diseases 0.000 description 12
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 12
- 235000004279 alanine Nutrition 0.000 description 11
- 235000012000 cholesterol Nutrition 0.000 description 11
- 238000010172 mouse model Methods 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 230000003827 upregulation Effects 0.000 description 10
- 108020004206 Gamma-glutamyltransferase Proteins 0.000 description 9
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 238000012453 sprague-dawley rat model Methods 0.000 description 9
- 230000002195 synergetic effect Effects 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 230000003247 decreasing effect Effects 0.000 description 8
- 238000001990 intravenous administration Methods 0.000 description 8
- 239000004576 sand Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- 241000282567 Macaca fascicularis Species 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 210000002216 heart Anatomy 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 210000005228 liver tissue Anatomy 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- 210000003491 skin Anatomy 0.000 description 7
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 7
- 241000282693 Cercopithecidae Species 0.000 description 6
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 6
- 206010067125 Liver injury Diseases 0.000 description 6
- 108010093662 Member 11 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 6
- 208000008589 Obesity Diseases 0.000 description 6
- 238000011529 RT qPCR Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 238000010201 enrichment analysis Methods 0.000 description 6
- 239000003925 fat Substances 0.000 description 6
- 235000019197 fats Nutrition 0.000 description 6
- 210000003494 hepatocyte Anatomy 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 210000003914 myeloid leukocyte Anatomy 0.000 description 6
- 235000020824 obesity Nutrition 0.000 description 6
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 6
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- IOIZWEJGGCZDOL-RQDYSCIWSA-N 7alpha-hydroxycholest-4-en-3-one Chemical compound C([C@H]1O)C2=CC(=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 IOIZWEJGGCZDOL-RQDYSCIWSA-N 0.000 description 5
- 102000011339 Bile salt export pump Human genes 0.000 description 5
- 238000011740 C57BL/6 mouse Methods 0.000 description 5
- 101100152865 Danio rerio thraa gene Proteins 0.000 description 5
- 238000013231 NASH rodent model Methods 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 208000010706 fatty liver disease Diseases 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 231100000234 hepatic damage Toxicity 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 230000008818 liver damage Effects 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 101150014006 thrA gene Proteins 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 101000857733 Homo sapiens G-protein coupled bile acid receptor 1 Proteins 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 230000020411 cell activation Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 235000009200 high fat diet Nutrition 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 230000028709 inflammatory response Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 230000037353 metabolic pathway Effects 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 238000013116 obese mouse model Methods 0.000 description 4
- 239000004006 olive oil Substances 0.000 description 4
- 235000008390 olive oil Nutrition 0.000 description 4
- 230000003285 pharmacodynamic effect Effects 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000012163 sequencing technique Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- WHBHBVVOGNECLV-OBQKJFGGSA-N 11-deoxycortisol Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WHBHBVVOGNECLV-OBQKJFGGSA-N 0.000 description 3
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 102100025353 G-protein coupled bile acid receptor 1 Human genes 0.000 description 3
- 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 3
- 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 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- 239000005913 Maltodextrin Substances 0.000 description 3
- 150000001204 N-oxides Chemical class 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 101150057833 THEG gene Proteins 0.000 description 3
- 241000949477 Toona ciliata Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000004534 cecum Anatomy 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 210000003405 ileum Anatomy 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229940035034 maltodextrin Drugs 0.000 description 3
- 238000002483 medication Methods 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 230000007115 recruitment Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000013207 serial dilution Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 229910052717 sulfur Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 102000004217 thyroid hormone receptors Human genes 0.000 description 3
- 108090000721 thyroid hormone receptors Proteins 0.000 description 3
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 2
- 102000043966 ABC-type transporter activity proteins Human genes 0.000 description 2
- 108010006533 ATP-Binding Cassette Transporters Proteins 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 208000027932 Collagen disease Diseases 0.000 description 2
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 2
- 102000003849 Cytochrome P450 Human genes 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 description 2
- 101710153349 Fibroblast growth factor 19 Proteins 0.000 description 2
- 229920002148 Gellan gum Polymers 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000617285 Homo sapiens Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000238367 Mya arenaria Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 2
- 102100021657 Tyrosine-protein phosphatase non-receptor type 6 Human genes 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 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 2
- 210000000941 bile Anatomy 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000009274 differential gene expression Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000010195 expression analysis Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229940014144 folate Drugs 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 235000010492 gellan gum Nutrition 0.000 description 2
- 239000000216 gellan gum Substances 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 150000002313 glycerolipids Chemical class 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 210000004024 hepatic stellate cell Anatomy 0.000 description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 description 2
- 125000005368 heteroarylthio group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 2
- 125000004468 heterocyclylthio group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 230000023404 leukocyte cell-cell adhesion Effects 0.000 description 2
- 230000011268 leukocyte chemotaxis Effects 0.000 description 2
- 230000021633 leukocyte mediated immunity Effects 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 238000012317 liver biopsy Methods 0.000 description 2
- 238000011670 long-evans rat Methods 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 208000008013 morphine dependence Diseases 0.000 description 2
- 150000002829 nitrogen Chemical class 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000006973 regulation of leukocyte migration Effects 0.000 description 2
- 229960003471 retinol Drugs 0.000 description 2
- 235000020944 retinol Nutrition 0.000 description 2
- 239000011607 retinol Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000004137 sphingolipid metabolism Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- 239000002676 xenobiotic agent Substances 0.000 description 2
- BHMLFPOTZYRDKA-IRXDYDNUSA-N (2s)-2-[(s)-(2-iodophenoxy)-phenylmethyl]morpholine Chemical compound IC1=CC=CC=C1O[C@@H](C=1C=CC=CC=1)[C@H]1OCCNC1 BHMLFPOTZYRDKA-IRXDYDNUSA-N 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 101150084399 37 gene Proteins 0.000 description 1
- 102100032645 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase Human genes 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 101150077253 APOA5 gene Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 101100328883 Arabidopsis thaliana COL1 gene Proteins 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101150017501 CCR5 gene Proteins 0.000 description 1
- 101150004010 CXCR3 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102100038637 Cytochrome P450 7A1 Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000957672 Homo sapiens Cytochrome P450 7A1 Proteins 0.000 description 1
- 101150058081 INHBE gene Proteins 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 108050006944 Keratin, type I cytoskeletal 18 Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 101150043981 LOXL2 gene Proteins 0.000 description 1
- 206010024438 Lichenification Diseases 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 101100400864 Mus musculus Abcb1a gene Proteins 0.000 description 1
- 101100390675 Mus musculus Fgf15 gene Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229910003202 NH4 Inorganic materials 0.000 description 1
- 101150004229 NR0B2 gene Proteins 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 108090001146 Nuclear Receptor Coactivator 1 Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 101150117945 PDGFB gene Proteins 0.000 description 1
- 101150108126 PLAU gene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241001319148 Pharmacis Species 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 241000435809 Sarea Species 0.000 description 1
- 206010039509 Scab Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 108010058254 Steroid 12-alpha-Hydroxylase Proteins 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101150009943 Tgfb3 gene Proteins 0.000 description 1
- 241001061127 Thione Species 0.000 description 1
- 101150021063 Timp2 gene Proteins 0.000 description 1
- 101150079992 Timp3 gene Proteins 0.000 description 1
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 1
- 102000005353 Tissue Inhibitor of Metalloproteinase-1 Human genes 0.000 description 1
- 102000005354 Tissue Inhibitor of Metalloproteinase-2 Human genes 0.000 description 1
- 102000005406 Tissue Inhibitor of Metalloproteinase-3 Human genes 0.000 description 1
- 101150082427 Tlr4 gene Proteins 0.000 description 1
- 208000025569 Tobacco Use disease Diseases 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 101150063830 abcB4 gene Proteins 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000013564 activation of immune response Effects 0.000 description 1
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 230000008236 biological pathway Effects 0.000 description 1
- 210000000476 body water Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000013262 cAMP assay Methods 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 230000006690 co-activation Effects 0.000 description 1
- 230000003081 coactivator Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000007691 collagen metabolic process Effects 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 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
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 230000009266 disease activity Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000001206 effect on leukocytes Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000009459 flexible packaging Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000008935 histological improvement Effects 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 102000051298 human GPBAR1 Human genes 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000033209 immune effector process Effects 0.000 description 1
- 230000008088 immune pathway Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000016788 immune system process Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 210000000066 myeloid cell Anatomy 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
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 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
- 230000003962 neuroinflammatory response Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 108010034596 procollagen Type III-N-terminal peptide Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000012857 radioactive material Substances 0.000 description 1
- 230000012121 regulation of immune response Effects 0.000 description 1
- 230000014038 regulation of leukocyte activation Effects 0.000 description 1
- 230000008024 regulation of leukocyte chemotaxis Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 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
- 230000028327 secretion Effects 0.000 description 1
- 101150096065 shp gene Proteins 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007905 soft elastic gelatin capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000026676 system process Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000003441 thioacyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 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
- A61K31/33—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202063024360P | 2020-05-13 | 2020-05-13 | |
| PCT/US2021/032085 WO2021231646A1 (en) | 2020-05-13 | 2021-05-12 | Combination treatment of liver disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL298144A true IL298144A (en) | 2023-01-01 |
Family
ID=78524975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL298144A IL298144A (en) | 2020-05-13 | 2021-05-12 | Combination treatment of liver disorders |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US20210379043A1 (enExample) |
| EP (1) | EP4149452A4 (enExample) |
| JP (1) | JP2023525571A (enExample) |
| KR (1) | KR20230024277A (enExample) |
| CN (1) | CN115811972A (enExample) |
| AU (1) | AU2021273487A1 (enExample) |
| BR (1) | BR112022023048A2 (enExample) |
| CA (1) | CA3183413A1 (enExample) |
| IL (1) | IL298144A (enExample) |
| MX (1) | MX2022014238A (enExample) |
| TW (1) | TW202207928A (enExample) |
| WO (1) | WO2021231646A1 (enExample) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN121081472A (zh) | 2018-12-13 | 2025-12-09 | 拓臻股份有限公司 | 一种THRβ受体激动剂化合物及其制备方法和用途 |
| CA3154488A1 (en) | 2019-08-23 | 2021-03-04 | Terns Pharmaceuticals, Inc. | Thyroid hormone receptor beta agonist compounds |
| CA3154391A1 (en) | 2019-09-12 | 2021-03-18 | Terns Pharmaceuticals, Inc. | Thyroid hormone receptor beta agonist compounds |
| PE20231096A1 (es) | 2020-08-25 | 2023-07-18 | Lilly Co Eli | Polimorfos de un inhibidor de ssao |
| WO2022165227A1 (en) * | 2021-02-01 | 2022-08-04 | Madrigal Pharmaceuticals, Inc. | Therapeutic combinations of rosuvastatin and resmetirom for the treatment of liver disorders or lipid disorders |
| TW202315608A (zh) * | 2021-07-06 | 2023-04-16 | 中國大陸商甘萊製藥有限公司 | 用於治療肝臟疾病的聯合治療 |
| TWI845975B (zh) * | 2021-07-06 | 2024-06-21 | 中國大陸商甘萊製藥有限公司 | 用於治療肝臟疾病的聯合治療 |
| AU2022387121A1 (en) * | 2021-11-11 | 2024-06-20 | Terns Pharmaceuticals, Inc. | Combination of a ssao inhibitor and thr-beta agonist for use in the treatment of liver disorders |
| MX2024005647A (es) * | 2021-11-11 | 2024-05-24 | Terns Pharmaceuticals Inc | Tratamiento de trastornos hepaticos con un agonista del thr-\03b2. |
| PE20252787A1 (es) | 2023-04-07 | 2025-12-22 | Terns Pharmaceuticals Inc | Combinacion que comprende un agonista de thr-beta y un agonista de glp-1r para su uso en el tratamiento de un trastorno hepatico o una enfermedad cardiometabolica |
| WO2026092583A1 (en) | 2024-10-30 | 2026-05-07 | Ascletis Pharma (China) Co., Limited | Thr-beta modulators, alone or in combination with glp-1r\gipr\gcgr modulators for the treatment of metabolic diseases and alopecia areata diseases |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI2170403T1 (sl) * | 2007-06-27 | 2014-07-31 | Quark Pharmaceuticals, Inc. | Sestavki in postopki za inhibicijo ekspresije pro-apoptotskih genov |
| TW200906823A (en) * | 2007-07-16 | 2009-02-16 | Lilly Co Eli | Compounds and methods for modulating FXR |
| CA2944139C (en) * | 2014-04-11 | 2020-11-03 | Cymabay Therapeutics, Inc. | Treatment of nafld and nash |
| JP7618384B2 (ja) * | 2017-02-21 | 2025-01-21 | ジェンフィ | Ｐｐａｒアゴニストとｆｘｒアゴニストとの組合せ |
| WO2018208707A1 (en) * | 2017-05-08 | 2018-11-15 | Neurovia, Inc. | Methods and compositions for treating demyelinating diseases |
| ES3029158T3 (en) * | 2018-06-12 | 2025-06-23 | Xizang Haisco Pharmaceutical Co Ltd | Thyroid hormone receptor agonists and uses thereof |
| EP3844156A4 (en) * | 2018-08-30 | 2022-06-08 | Terns Pharmaceuticals, Inc. | TREATMENT OF LIVER DISEASES |
| US20220047553A1 (en) * | 2018-09-18 | 2022-02-17 | Metacrine, Inc. | Farnesoid x receptor agonists for the treatment of disease |
| CN121081472A (zh) * | 2018-12-13 | 2025-12-09 | 拓臻股份有限公司 | 一种THRβ受体激动剂化合物及其制备方法和用途 |
-
2021
- 2021-05-12 WO PCT/US2021/032085 patent/WO2021231646A1/en not_active Ceased
- 2021-05-12 JP JP2022568965A patent/JP2023525571A/ja active Pending
- 2021-05-12 AU AU2021273487A patent/AU2021273487A1/en active Pending
- 2021-05-12 US US17/318,994 patent/US20210379043A1/en not_active Abandoned
- 2021-05-12 EP EP21803928.7A patent/EP4149452A4/en active Pending
- 2021-05-12 CN CN202180047741.3A patent/CN115811972A/zh active Pending
- 2021-05-12 KR KR1020227043095A patent/KR20230024277A/ko not_active Ceased
- 2021-05-12 IL IL298144A patent/IL298144A/en unknown
- 2021-05-12 MX MX2022014238A patent/MX2022014238A/es unknown
- 2021-05-12 CA CA3183413A patent/CA3183413A1/en active Pending
- 2021-05-12 BR BR112022023048A patent/BR112022023048A2/pt unknown
- 2021-05-13 TW TW110117355A patent/TW202207928A/zh unknown
-
2023
- 2023-01-20 US US18/157,216 patent/US20240000765A1/en not_active Abandoned
-
2024
- 2024-06-03 US US18/732,162 patent/US20240316025A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| MX2022014238A (es) | 2023-04-11 |
| TW202207928A (zh) | 2022-03-01 |
| JP2023525571A (ja) | 2023-06-16 |
| US20240316025A1 (en) | 2024-09-26 |
| CN115811972A (zh) | 2023-03-17 |
| EP4149452A1 (en) | 2023-03-22 |
| AU2021273487A1 (en) | 2023-01-05 |
| CA3183413A1 (en) | 2021-11-18 |
| WO2021231646A1 (en) | 2021-11-18 |
| KR20230024277A (ko) | 2023-02-20 |
| BR112022023048A2 (pt) | 2022-12-20 |
| US20210379043A1 (en) | 2021-12-09 |
| US20240000765A1 (en) | 2024-01-04 |
| EP4149452A4 (en) | 2024-05-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20240316025A1 (en) | Combination treatment of liver disorders | |
| IL298145A (en) | Combined treatment of liver disorders | |
| IL290727B2 (en) | Formulation for inhibiting formation of 5-ht 2b agonists and methods of using same | |
| US20150283113A1 (en) | Combination therapies for the treatment of alzheimer's disease and related disorders | |
| JP2024544528A (ja) | 肝障害の治療に使用するためのｓｓａｏ阻害剤及びｔｈｒ－ベータアゴニストの組合せ | |
| US20100222376A1 (en) | Chelerythrine, analogs thereof and their use in the treatment of bipolar disorder and other cognitive disorders | |
| US20130123248A1 (en) | Pharmacological modulation of positive ampa receptor modulator effects on neurotrophin expression | |
| IL294031A (en) | History of benzodiazepines, preparations and methods for the treatment of cognitive impairment | |
| IL291818A (en) | Combinations of gaba-a receptor positive allosteric modulators and nmda antagonists, nmda negative allosteric modulators or nmda partial agonists | |
| IL292459A (en) | Treatment of liver disorders | |
| JP6196638B2 (ja) | 麻痺性貝毒 | |
| AU2021328824A1 (en) | Therapeutic agent for fatty liver disease | |
| US20240148833A1 (en) | Composition comprising glp-1 receptor agonist and acat inhibitor | |
| IL287727B1 (en) | Use of phenoxypropylamine compounds to treat depression | |
| US20200276186A1 (en) | Use of morphinans for treating cocaine addiction, pruritis, and seizure disorders | |
| IL303521A (en) | Masitinib for the treatment of alzheimer's disease | |
| RU2849641C1 (ru) | Терапевтическое средство против жировой болезни печени | |
| RU2588133C2 (ru) | Ниациновые миметики и способ их использования |