TW201936189A - 用於使用fxr激動劑之方法 - Google Patents
用於使用fxr激動劑之方法 Download PDFInfo
- Publication number
- TW201936189A TW201936189A TW107142391A TW107142391A TW201936189A TW 201936189 A TW201936189 A TW 201936189A TW 107142391 A TW107142391 A TW 107142391A TW 107142391 A TW107142391 A TW 107142391A TW 201936189 A TW201936189 A TW 201936189A
- Authority
- TW
- Taiwan
- Prior art keywords
- tropine
- dose
- liver
- nash
- treatment
- Prior art date
Links
- 238000000034 method Methods 0.000 title abstract description 39
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 title description 19
- 208000019423 liver disease Diseases 0.000 claims abstract description 60
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 135
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 102
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 claims description 99
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 claims description 99
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 claims description 99
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 claims description 99
- 238000011282 treatment Methods 0.000 claims description 56
- 150000001413 amino acids Chemical class 0.000 claims description 46
- 206010016654 Fibrosis Diseases 0.000 claims description 44
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 42
- 230000001404 mediated effect Effects 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 claims description 23
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 claims description 23
- 206010008635 Cholestasis Diseases 0.000 claims description 23
- 229940043259 farnesol Drugs 0.000 claims description 23
- 229930002886 farnesol Natural products 0.000 claims description 23
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 claims description 23
- 201000001883 cholelithiasis Diseases 0.000 claims description 22
- 230000007882 cirrhosis Effects 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- 230000002265 prevention Effects 0.000 claims description 15
- 210000000013 bile duct Anatomy 0.000 claims description 13
- 239000002552 dosage form Substances 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 12
- 206010056375 Bile duct obstruction Diseases 0.000 claims description 11
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 208000027418 Wounds and injury Diseases 0.000 claims description 11
- 230000006378 damage Effects 0.000 claims description 11
- 208000001130 gallstones Diseases 0.000 claims description 11
- 208000014674 injury Diseases 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 3
- 102100038495 Bile acid receptor Human genes 0.000 abstract description 39
- 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 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 15
- 229940070126 tropifexor Drugs 0.000 abstract description 11
- 101150027485 NR1H4 gene Proteins 0.000 abstract 2
- 229940024606 amino acid Drugs 0.000 description 45
- 235000001014 amino acid Nutrition 0.000 description 45
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 37
- 230000004761 fibrosis Effects 0.000 description 26
- 210000004185 liver Anatomy 0.000 description 26
- 201000007909 oculocutaneous albinism Diseases 0.000 description 22
- 102000005962 receptors Human genes 0.000 description 22
- 108020003175 receptors Proteins 0.000 description 22
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 15
- 108010082126 Alanine transaminase Proteins 0.000 description 15
- 206010067125 Liver injury Diseases 0.000 description 14
- 208000035475 disorder Diseases 0.000 description 14
- 238000011269 treatment regimen Methods 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 13
- 231100000359 cholestasis Toxicity 0.000 description 12
- 230000007870 cholestasis Effects 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 231100000753 hepatic injury Toxicity 0.000 description 12
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 11
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 11
- 241000700159 Rattus Species 0.000 description 11
- 235000005911 diet Nutrition 0.000 description 11
- 230000037213 diet Effects 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 9
- JBDOSUUXMYMWQH-UHFFFAOYSA-N 1-naphthyl isothiocyanate Chemical compound C1=CC=C2C(N=C=S)=CC=CC2=C1 JBDOSUUXMYMWQH-UHFFFAOYSA-N 0.000 description 8
- 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 8
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 8
- 239000003613 bile acid Substances 0.000 description 7
- 239000000090 biomarker Substances 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- 231100000673 dose–response relationship Toxicity 0.000 description 7
- LFULEKSKNZEWOE-UHFFFAOYSA-N propanil Chemical compound CCC(=O)NC1=CC=C(Cl)C(Cl)=C1 LFULEKSKNZEWOE-UHFFFAOYSA-N 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 206010019670 Hepatic function abnormal Diseases 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 208000003251 Pruritus Diseases 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 230000007863 steatosis Effects 0.000 description 6
- 231100000240 steatosis hepatitis Toxicity 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 230000008021 deposition Effects 0.000 description 5
- 238000012317 liver biopsy Methods 0.000 description 5
- 239000000902 placebo Substances 0.000 description 5
- 229940068196 placebo Drugs 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- 206010003445 Ascites Diseases 0.000 description 4
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229930182480 glucuronide Natural products 0.000 description 4
- 230000008935 histological improvement Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 208000028774 intestinal disease Diseases 0.000 description 4
- 230000007803 itching Effects 0.000 description 4
- 235000012054 meals Nutrition 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 229960003080 taurine Drugs 0.000 description 4
- 150000003626 triacylglycerols Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 description 3
- 241000282472 Canis lupus familiaris Species 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
- 239000005715 Fructose Substances 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 150000008134 glucuronides Chemical class 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 235000015263 low fat diet Nutrition 0.000 description 3
- 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 3
- 238000011002 quantification Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012360 testing method Methods 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
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 206010010071 Coma Diseases 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- 102100031734 Fibroblast growth factor 19 Human genes 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
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 238000013234 NASH mouse model Methods 0.000 description 2
- 238000013231 NASH rodent model Methods 0.000 description 2
- 206010038743 Restlessness Diseases 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 230000033228 biological regulation Effects 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
- 230000001684 chronic effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000004992 fission Effects 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 208000018191 liver inflammation Diseases 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 2
- 229960001601 obeticholic acid Drugs 0.000 description 2
- 238000002559 palpation Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 231100000041 toxicology testing Toxicity 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- 102100040121 Allograft inflammatory factor 1 Human genes 0.000 description 1
- 241000842962 Apoda limacodes Species 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 206010069703 Bile acid malabsorption Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 241000949473 Correa Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 1
- 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 1
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 101000890626 Homo sapiens Allograft inflammatory factor 1 Proteins 0.000 description 1
- 101000945357 Homo sapiens Collagen alpha-1(I) chain Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 101150077804 TIMP1 gene Proteins 0.000 description 1
- 102000005353 Tissue Inhibitor of Metalloproteinase-1 Human genes 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000000739 chaotic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 235000020940 control diet Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940029980 drug used in diabetes Drugs 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 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
- 210000000981 epithelium Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- -1 glucuronide Glycoside Chemical class 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 206010020745 hyperreflexia Diseases 0.000 description 1
- 230000035859 hyperreflexia Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010984 neurological examination Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000013424 sirius red staining Methods 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010692 trans-unsaturated fatty acids Nutrition 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762593084P | 2017-11-30 | 2017-11-30 | |
| US62/593,084 | 2017-11-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW201936189A true TW201936189A (zh) | 2019-09-16 |
Family
ID=64959384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW107142391A TW201936189A (zh) | 2017-11-30 | 2018-11-28 | 用於使用fxr激動劑之方法 |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US20210361638A1 (https=) |
| EP (1) | EP3716977A1 (https=) |
| JP (1) | JP2021504370A (https=) |
| KR (1) | KR20200094175A (https=) |
| CN (1) | CN111356458A (https=) |
| AU (1) | AU2018376904B2 (https=) |
| CA (1) | CA3081656A1 (https=) |
| IL (1) | IL274747A (https=) |
| MX (1) | MX2020005557A (https=) |
| RU (1) | RU2020121222A (https=) |
| TW (1) | TW201936189A (https=) |
| WO (1) | WO2019106550A1 (https=) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021014349A1 (en) * | 2019-07-23 | 2021-01-28 | Novartis Ag | Treatment comprising fxr agonists |
| WO2021064575A1 (en) * | 2019-09-30 | 2021-04-08 | Novartis Ag | Treatment comprising the use of fxr agonists |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL1734970T3 (pl) * | 2004-03-12 | 2015-05-29 | Intercept Pharmaceuticals Inc | Leczenie zwłóknienia z zastosowaniem ligandów FXR |
| CU24152B1 (es) | 2010-12-20 | 2016-02-29 | Irm Llc | 1,2 oxazol-8-azabiciclo[3,2,1]octano 8 il como moduladores de fxr |
| ES2902404T3 (es) * | 2016-02-22 | 2022-03-28 | Novartis Ag | Métodos para utilizar agonistas de fxr. |
| ES2862194T3 (es) * | 2016-02-22 | 2021-10-07 | Novartis Ag | Métodos para usar agonistas del FXR |
| MX384205B (es) * | 2016-02-22 | 2025-03-14 | Novartis Ag | Metodos para usar agonistas de fxr. |
| AR114930A1 (es) * | 2017-09-12 | 2020-11-11 | Novartis Ag | Composición farmacéutica |
-
2018
- 2018-11-28 EP EP18830302.8A patent/EP3716977A1/en not_active Withdrawn
- 2018-11-28 US US16/767,078 patent/US20210361638A1/en not_active Abandoned
- 2018-11-28 KR KR1020207017973A patent/KR20200094175A/ko not_active Ceased
- 2018-11-28 RU RU2020121222A patent/RU2020121222A/ru unknown
- 2018-11-28 WO PCT/IB2018/059383 patent/WO2019106550A1/en not_active Ceased
- 2018-11-28 US US16/202,637 patent/US20190161483A1/en not_active Abandoned
- 2018-11-28 MX MX2020005557A patent/MX2020005557A/es unknown
- 2018-11-28 AU AU2018376904A patent/AU2018376904B2/en not_active Ceased
- 2018-11-28 TW TW107142391A patent/TW201936189A/zh unknown
- 2018-11-28 CN CN201880074342.4A patent/CN111356458A/zh active Pending
- 2018-11-28 CA CA3081656A patent/CA3081656A1/en active Pending
- 2018-11-28 JP JP2020528867A patent/JP2021504370A/ja active Pending
-
2020
- 2020-05-18 IL IL274747A patent/IL274747A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US20190161483A1 (en) | 2019-05-30 |
| AU2018376904A1 (en) | 2020-05-21 |
| RU2020121222A3 (https=) | 2022-04-19 |
| JP2021504370A (ja) | 2021-02-15 |
| CN111356458A (zh) | 2020-06-30 |
| RU2020121222A (ru) | 2021-12-30 |
| WO2019106550A1 (en) | 2019-06-06 |
| EP3716977A1 (en) | 2020-10-07 |
| MX2020005557A (es) | 2020-08-20 |
| KR20200094175A (ko) | 2020-08-06 |
| CA3081656A1 (en) | 2019-06-06 |
| US20210361638A1 (en) | 2021-11-25 |
| AU2018376904B2 (en) | 2021-07-22 |
| IL274747A (en) | 2020-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11517572B2 (en) | Killing senescent cells and treating senescence-associated conditions using a SRC inhibitor and a flavonoid | |
| TWI735546B (zh) | 使用fxr促效劑之方法 | |
| Xu et al. | Gut-liver axis modulation of Panax notoginseng saponins in nonalcoholic fatty liver disease | |
| Fucho et al. | ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis | |
| Sims-Robinson et al. | The role of endoplasmic reticulum stress in hippocampal insulin resistance | |
| AU2020203316A1 (en) | Novel regimes of FXR agonists | |
| JP2019530696A (ja) | 線維性、硬変性の疾患もしくは障害を治療または予防するためのｆｘｒアゴニストを含む組合せ組成物 | |
| WO2019053582A1 (en) | COMBINATIONS HAVING FXR AGONISTS | |
| Mai et al. | Silibinin ameliorates deoxycholic acid-induced pyroptosis in steatotic HepG2 cells by inhibiting NLRP3 inflammasome activation | |
| Lee et al. | DWN12088, A Prolyl-tRNA synthetase inhibitor, alleviates hepatic injury in nonalcoholic steatohepatitis | |
| TW201936189A (zh) | 用於使用fxr激動劑之方法 | |
| Yoo et al. | DA-1241, a GPR119 agonist, ameliorates fatty liver through the upregulation of TFEB-mediated autophagy | |
| Hossain et al. | KIT-13, a novel plasmalogen derivative, attenuates neuroinflammation and amplifies cognition | |
| JP2022550312A (ja) | Ｆｘｒアゴニストの使用を含む処置 | |
| Barbut et al. | Anti-aging properties of the aminosterols of the dogfish shark | |
| TWI906348B (zh) | 脂肪性肝疾病之治療劑 | |
| Wu et al. | STAT3 inhibitors combined with retinol binding protein 4 complex ameliorate DEN-induced liver carcinogenesis in mice and induce apoptosis via GRP78/ATF6/CHOP signaling pathway | |
| JP2019524860A (ja) | 非アルコール性脂肪肝疾患の治療法 |