TW202135812A - 使用整聯蛋白抑制劑組合治療肝臟疾病 - Google Patents
使用整聯蛋白抑制劑組合治療肝臟疾病 Download PDFInfo
- Publication number
- TW202135812A TW202135812A TW109145129A TW109145129A TW202135812A TW 202135812 A TW202135812 A TW 202135812A TW 109145129 A TW109145129 A TW 109145129A TW 109145129 A TW109145129 A TW 109145129A TW 202135812 A TW202135812 A TW 202135812A
- Authority
- TW
- Taiwan
- Prior art keywords
- liver
- compound
- fibrosis
- nash
- combination
- Prior art date
Links
- 208000019423 liver disease Diseases 0.000 title claims abstract description 63
- 108010044426 integrins Proteins 0.000 title description 34
- 102000006495 integrins Human genes 0.000 title description 34
- 239000003112 inhibitor Substances 0.000 title description 21
- 238000011284 combination treatment Methods 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 52
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 claims abstract description 46
- 229940125798 integrin inhibitor Drugs 0.000 claims abstract description 40
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 31
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 117
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 81
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 69
- 239000003613 bile acid Substances 0.000 claims description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 46
- 206010016654 Fibrosis Diseases 0.000 claims description 44
- 210000004185 liver Anatomy 0.000 claims description 44
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 43
- 239000000890 drug combination Substances 0.000 claims description 34
- 230000004761 fibrosis Effects 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 19
- 150000001413 amino acids Chemical class 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 230000003176 fibrotic effect Effects 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 230000007882 cirrhosis Effects 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000000750 progressive effect Effects 0.000 claims description 7
- 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 claims description 6
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 208000037319 Hepatitis infectious Diseases 0.000 claims description 4
- 208000005252 hepatitis A Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940000425 combination drug Drugs 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 abstract description 83
- 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 3
- 229940070126 tropifexor Drugs 0.000 abstract description 2
- GELVLHVQVRSFAY-FQEVSTJZSA-N (2S)-2-[(4-methyloxane-4-carbonyl)amino]-9-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)nonanoic acid Chemical compound CC1(CCOCC1)C(=O)N[C@H](C(=O)O)CCCCCCCC1=NC=2NCCCC=2C=C1 GELVLHVQVRSFAY-FQEVSTJZSA-N 0.000 abstract 1
- VYLOOGHLKSNNEK-UHFFFAOYSA-N 2-[3-[[5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound S1C2=CC(C(=O)O)=CC(F)=C2N=C1N1C(C2)CCC1CC2OCC1=C(C2CC2)ON=C1C1=CC=CC=C1OC(F)(F)F VYLOOGHLKSNNEK-UHFFFAOYSA-N 0.000 abstract 1
- 238000011282 treatment Methods 0.000 description 32
- 150000001875 compounds Chemical class 0.000 description 19
- 230000000694 effects Effects 0.000 description 17
- 208000035475 disorder Diseases 0.000 description 16
- 206010008635 Cholestasis Diseases 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 14
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 13
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 13
- 206010019708 Hepatic steatosis Diseases 0.000 description 13
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 102000008186 Collagen Human genes 0.000 description 11
- 108010035532 Collagen Proteins 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 230000007870 cholestasis Effects 0.000 description 11
- 231100000359 cholestasis Toxicity 0.000 description 11
- 229920001436 collagen Polymers 0.000 description 10
- 208000006454 hepatitis Diseases 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 210000003494 hepatocyte Anatomy 0.000 description 9
- 208000028774 intestinal disease Diseases 0.000 description 9
- 208000018191 liver inflammation Diseases 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 231100000240 steatosis hepatitis Toxicity 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 8
- 230000003510 anti-fibrotic effect Effects 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 201000001883 cholelithiasis Diseases 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 230000007850 degeneration Effects 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 8
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 7
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 7
- -1 acyl glucuronide Chemical class 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 7
- 230000037213 diet Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000902 placebo Substances 0.000 description 7
- 229940068196 placebo Drugs 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 230000007863 steatosis Effects 0.000 description 7
- 238000002054 transplantation Methods 0.000 description 7
- 102100038495 Bile acid receptor Human genes 0.000 description 6
- 208000004930 Fatty Liver Diseases 0.000 description 6
- 102100031734 Fibroblast growth factor 19 Human genes 0.000 description 6
- 101000846394 Homo sapiens Fibroblast growth factor 19 Proteins 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 5
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 5
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 210000000013 bile duct Anatomy 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 210000000936 intestine Anatomy 0.000 description 5
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 230000007310 pathophysiology Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- CDKIEBFIMCSCBB-UHFFFAOYSA-N 1-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-3-(1-methyl-2-phenylpyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one;hydrochloride Chemical class Cl.C1C=2C=C(OC)C(OC)=CC=2CCN1C(=O)C=CC(C1=CC=CN=C1N1C)=C1C1=CC=CC=C1 CDKIEBFIMCSCBB-UHFFFAOYSA-N 0.000 description 4
- 108070000005 Bile acid receptors Proteins 0.000 description 4
- 206010056375 Bile duct obstruction Diseases 0.000 description 4
- 238000013236 CDAHFD model Methods 0.000 description 4
- 208000017667 Chronic Disease Diseases 0.000 description 4
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 230000035508 accumulation Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000011260 co-administration Methods 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 208000001130 gallstones Diseases 0.000 description 4
- 229930182480 glucuronide Natural products 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 210000005228 liver tissue Anatomy 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229960003080 taurine Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YDHAGPCZRFQPOI-NRFANRHFSA-N (3s)-3-(3-bromo-5-tert-butylphenyl)-3-[[2-[[3-hydroxy-5-[(5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino]benzoyl]amino]acetyl]amino]propanoic acid Chemical compound CC(C)(C)C1=CC(Br)=CC([C@H](CC(O)=O)NC(=O)CNC(=O)C=2C=C(NC=3NCC(O)CN=3)C=C(O)C=2)=C1 YDHAGPCZRFQPOI-NRFANRHFSA-N 0.000 description 3
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 3
- 241000725101 Clea Species 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101001046677 Homo sapiens Integrin alpha-V Proteins 0.000 description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 3
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 3
- 238000013234 NASH mouse model Methods 0.000 description 3
- 208000034189 Sclerosis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 235000021590 normal diet Nutrition 0.000 description 3
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical group 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 3
- 201000002793 renal fibrosis Diseases 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 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 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 102000011339 Bile salt export pump Human genes 0.000 description 2
- 208000021130 Bilirubin encephalopathy Diseases 0.000 description 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 2
- 108700012434 CCL3 Proteins 0.000 description 2
- 101150008656 COL1A1 gene Proteins 0.000 description 2
- 102000000013 Chemokine CCL3 Human genes 0.000 description 2
- 108010055166 Chemokine CCL5 Proteins 0.000 description 2
- 206010049055 Cholestasis of pregnancy Diseases 0.000 description 2
- 101150008975 Col3a1 gene Proteins 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 description 2
- 206010019663 Hepatic failure Diseases 0.000 description 2
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 102100022337 Integrin alpha-V Human genes 0.000 description 2
- 108010040765 Integrin alphaV Proteins 0.000 description 2
- 206010023138 Jaundice neonatal Diseases 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 108010093662 Member 11 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 2
- 102000005741 Metalloproteases Human genes 0.000 description 2
- 108010006035 Metalloproteases Proteins 0.000 description 2
- 101100390675 Mus musculus Fgf15 gene Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 201000006346 Neonatal Jaundice Diseases 0.000 description 2
- 102100023172 Nuclear receptor subfamily 0 group B member 2 Human genes 0.000 description 2
- 208000012868 Overgrowth Diseases 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000002300 anti-fibrosis Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 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 2
- 206010009887 colitis Diseases 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 101150100705 ehhadh gene Proteins 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 238000010195 expression analysis Methods 0.000 description 2
- 230000004129 fatty acid metabolism Effects 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 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 2
- 208000001024 intrahepatic cholestasis Diseases 0.000 description 2
- 230000007872 intrahepatic cholestasis Effects 0.000 description 2
- 208000006663 kernicterus Diseases 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 231100000835 liver failure Toxicity 0.000 description 2
- 208000007903 liver failure Diseases 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 108010003814 member 2 group B nuclear receptor subfamily 0 Proteins 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000000651 myofibroblast Anatomy 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 235000016236 parenteral nutrition Nutrition 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 210000002824 peroxisome Anatomy 0.000 description 2
- 208000007232 portal hypertension Diseases 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 208000010157 sclerosing cholangitis Diseases 0.000 description 2
- 230000002784 sclerotic effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- ADHAUWMNDHMUMH-UHFFFAOYSA-L 2-[bis(carboxylatomethyl)amino]acetate;hydron;nickel(2+) Chemical compound [Ni+2].OC(=O)CN(CC([O-])=O)CC([O-])=O ADHAUWMNDHMUMH-UHFFFAOYSA-L 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 101150077457 ACOX1 gene Proteins 0.000 description 1
- 101150073604 Adgre1 gene Proteins 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 206010069703 Bile acid malabsorption Diseases 0.000 description 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101150072801 COL1A2 gene Proteins 0.000 description 1
- 108090000835 CX3C Chemokine Receptor 1 Proteins 0.000 description 1
- 102100039196 CX3C chemokine receptor 1 Human genes 0.000 description 1
- 101150091877 Ccn2 gene Proteins 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 102000015225 Connective Tissue Growth Factor Human genes 0.000 description 1
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 102100020997 Fractalkine Human genes 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 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 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
- 239000007821 HATU Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 1
- 101000854520 Homo sapiens Fractalkine Proteins 0.000 description 1
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 1
- 101000833892 Homo sapiens Peroxisomal acyl-coenzyme A oxidase 1 Proteins 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- 102100025136 Macrosialin Human genes 0.000 description 1
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 1
- 102000000424 Matrix Metalloproteinase 2 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108050006599 Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 238000013231 NASH rodent model Methods 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 102100026798 Peroxisomal acyl-coenzyme A oxidase 1 Human genes 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 101000833887 Yarrowia lipolytica (strain CLIB 122 / E 150) Acyl-coenzyme A oxidase 1 Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000013228 adult male C57BL/6J mice Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 238000011325 biochemical measurement Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 210000004900 c-terminal fragment Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000005465 channeling Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 230000008713 feedback mechanism Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000784 hepatotoxin Toxicity 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 235000020997 lean meat Nutrition 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
- 238000007477 logistic regression Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000020925 non fasting Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000012755 real-time RT-PCR analysis Methods 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000013424 sirius red staining Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 239000008227 sterile water for injection Substances 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
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Images
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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic 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
- A61K31/435—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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (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)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962951615P | 2019-12-20 | 2019-12-20 | |
| US62/951,615 | 2019-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202135812A true TW202135812A (zh) | 2021-10-01 |
Family
ID=74186956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW109145129A TW202135812A (zh) | 2019-12-20 | 2020-12-18 | 使用整聯蛋白抑制劑組合治療肝臟疾病 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20230055657A1 (enExample) |
| EP (1) | EP4076455A1 (enExample) |
| JP (1) | JP2023507387A (enExample) |
| KR (1) | KR20220121838A (enExample) |
| CN (1) | CN114929219A (enExample) |
| AR (1) | AR120859A1 (enExample) |
| AU (1) | AU2020405182B2 (enExample) |
| CA (1) | CA3165000A1 (enExample) |
| IL (1) | IL293895A (enExample) |
| TW (1) | TW202135812A (enExample) |
| WO (1) | WO2021127483A1 (enExample) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220220206A1 (en) * | 2019-05-20 | 2022-07-14 | Mayo Foundation For Medical Education And Research | Treating chronic liver disease |
| US20230060422A1 (en) * | 2019-12-20 | 2023-03-02 | Novartis Ag | Combination treatment of liver diseases using integrin inhibitors |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| EP3509590A4 (en) * | 2016-09-07 | 2020-12-02 | Pliant Therapeutics, Inc. | N-ACYL AMINO ACID COMPOUNDS AND METHODS OF USE |
| RU2019110780A (ru) * | 2016-09-14 | 2020-10-15 | Новартис Аг | Комбинация агонистов fxr |
| TWI841573B (zh) * | 2018-06-27 | 2024-05-11 | 美商普萊恩醫療公司 | 具有未分支連接子之胺基酸化合物及使用方法 |
| CN118852054A (zh) * | 2019-02-06 | 2024-10-29 | 阿尔比里奥公司 | 苯并硫杂二氮杂环庚三烯化合物及其用作胆汁酸调节剂的用途 |
-
2020
- 2020-12-18 TW TW109145129A patent/TW202135812A/zh unknown
- 2020-12-18 EP EP20842496.0A patent/EP4076455A1/en not_active Withdrawn
- 2020-12-18 AU AU2020405182A patent/AU2020405182B2/en not_active Ceased
- 2020-12-18 KR KR1020227024756A patent/KR20220121838A/ko active Pending
- 2020-12-18 CA CA3165000A patent/CA3165000A1/en active Pending
- 2020-12-18 WO PCT/US2020/066079 patent/WO2021127483A1/en not_active Ceased
- 2020-12-18 IL IL293895A patent/IL293895A/en unknown
- 2020-12-18 CN CN202080088263.6A patent/CN114929219A/zh active Pending
- 2020-12-18 JP JP2022537270A patent/JP2023507387A/ja active Pending
- 2020-12-18 US US17/786,499 patent/US20230055657A1/en not_active Abandoned
- 2020-12-21 AR ARP200103597A patent/AR120859A1/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2020405182B2 (en) | 2024-03-14 |
| EP4076455A1 (en) | 2022-10-26 |
| CA3165000A1 (en) | 2021-06-24 |
| JP2023507387A (ja) | 2023-02-22 |
| AU2020405182A1 (en) | 2022-07-07 |
| IL293895A (en) | 2022-08-01 |
| KR20220121838A (ko) | 2022-09-01 |
| US20230055657A1 (en) | 2023-02-23 |
| CN114929219A (zh) | 2022-08-19 |
| AR120859A1 (es) | 2022-03-23 |
| WO2021127483A1 (en) | 2021-06-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6941109B2 (ja) | Fxrアゴニストを使用するための方法 | |
| KR20220038368A (ko) | Fxr 작용제를 이용하는 간 질환의 병용 치료 | |
| US20210283105A1 (en) | Novel regimes of fxr agonists | |
| JP6878596B2 (ja) | Fxrアゴニストの組合せ | |
| KR20190062501A (ko) | 섬유증, 간경화 질환 또는 질병을 치료 또는 예방하기 위한 fxr 작용제를 포함하는 조합 조성물 | |
| US20200276178A1 (en) | Combinations comprising fxr agonists | |
| TW202135811A (zh) | 使用整聯蛋白抑制劑組合治療肝臟疾病 | |
| TW202135812A (zh) | 使用整聯蛋白抑制劑組合治療肝臟疾病 | |
| JP2022548617A (ja) | Fxrアゴニストを含む処置 |