JP7224294B2 - 組合せ療法のための医薬組成物 - Google Patents
組合せ療法のための医薬組成物 Download PDFInfo
- Publication number
- JP7224294B2 JP7224294B2 JP2019541179A JP2019541179A JP7224294B2 JP 7224294 B2 JP7224294 B2 JP 7224294B2 JP 2019541179 A JP2019541179 A JP 2019541179A JP 2019541179 A JP2019541179 A JP 2019541179A JP 7224294 B2 JP7224294 B2 JP 7224294B2
- Authority
- JP
- Japan
- Prior art keywords
- fibrosis
- group
- ntz
- combination
- liver
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title description 6
- 238000002648 combination therapy Methods 0.000 title 1
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 claims description 117
- 206010016654 Fibrosis Diseases 0.000 claims description 116
- 229960002480 nitazoxanide Drugs 0.000 claims description 107
- 230000004761 fibrosis Effects 0.000 claims description 98
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 58
- 150000001875 compounds Chemical class 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 40
- 210000004185 liver Anatomy 0.000 claims description 36
- 230000003176 fibrotic effect Effects 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims description 17
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims description 17
- 239000002307 peroxisome proliferator activated receptor agonist Substances 0.000 claims description 17
- 229940126033 PPAR agonist Drugs 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- -1 Nodal Proteins 0.000 claims description 13
- 210000004027 cell Anatomy 0.000 claims description 13
- 210000004072 lung Anatomy 0.000 claims description 8
- 230000002496 gastric effect Effects 0.000 claims description 7
- 210000003734 kidney Anatomy 0.000 claims description 7
- 210000002216 heart Anatomy 0.000 claims description 6
- 210000000936 intestine Anatomy 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 210000003491 skin Anatomy 0.000 claims description 6
- 210000004872 soft tissue Anatomy 0.000 claims description 6
- 102000005862 Angiotensin II Human genes 0.000 claims description 5
- 101800000733 Angiotensin-2 Proteins 0.000 claims description 5
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 5
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 claims description 5
- 239000012190 activator Substances 0.000 claims description 5
- 229950006323 angiotensin ii Drugs 0.000 claims description 5
- 210000000845 cartilage Anatomy 0.000 claims description 5
- 210000000653 nervous system Anatomy 0.000 claims description 5
- 210000002435 tendon Anatomy 0.000 claims description 5
- 239000013543 active substance Substances 0.000 claims description 4
- 210000001185 bone marrow Anatomy 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 210000003205 muscle Anatomy 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 102000005962 receptors Human genes 0.000 claims description 4
- 108020003175 receptors Proteins 0.000 claims description 4
- 101000777550 Homo sapiens CCN family member 2 Proteins 0.000 claims description 3
- 101000659879 Homo sapiens Thrombospondin-1 Proteins 0.000 claims description 3
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 claims description 3
- 102100033456 TGF-beta receptor type-1 Human genes 0.000 claims description 3
- 101710084191 TGF-beta receptor type-1 Proteins 0.000 claims description 3
- 102100036034 Thrombospondin-1 Human genes 0.000 claims description 3
- 210000004100 adrenal gland Anatomy 0.000 claims description 3
- 239000000443 aerosol Substances 0.000 claims description 3
- 210000001367 artery Anatomy 0.000 claims description 3
- 210000003445 biliary tract Anatomy 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 210000001072 colon Anatomy 0.000 claims description 3
- 210000003038 endothelium Anatomy 0.000 claims description 3
- 210000002615 epidermis Anatomy 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 102000006495 integrins Human genes 0.000 claims description 3
- 108010044426 integrins Proteins 0.000 claims description 3
- 239000003921 oil Substances 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 210000001672 ovary Anatomy 0.000 claims description 3
- 210000000496 pancreas Anatomy 0.000 claims description 3
- 229960003073 pirfenidone Drugs 0.000 claims description 3
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 230000002459 sustained effect Effects 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 210000001550 testis Anatomy 0.000 claims description 3
- 210000004291 uterus Anatomy 0.000 claims description 3
- 210000003462 vein Anatomy 0.000 claims description 3
- 102100026802 72 kDa type IV collagenase Human genes 0.000 claims description 2
- 108010059616 Activins Proteins 0.000 claims description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 2
- 102100031168 CCN family member 2 Human genes 0.000 claims description 2
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 claims description 2
- 101000990902 Homo sapiens Matrix metalloproteinase-9 Proteins 0.000 claims description 2
- 108010004250 Inhibins Proteins 0.000 claims description 2
- 102000002746 Inhibins Human genes 0.000 claims description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 2
- 239000000488 activin Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000893 inhibin Substances 0.000 claims description 2
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 claims description 2
- 229960004378 nintedanib Drugs 0.000 claims description 2
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 claims description 2
- 229960003787 sorafenib Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 108010005853 Anti-Mullerian Hormone Proteins 0.000 claims 1
- 102100026818 Inhibin beta E chain Human genes 0.000 claims 1
- 102100030173 Muellerian-inhibiting factor Human genes 0.000 claims 1
- 239000000868 anti-mullerian hormone Substances 0.000 claims 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 119
- 230000007882 cirrhosis Effects 0.000 description 62
- 235000005911 diet Nutrition 0.000 description 37
- 230000037213 diet Effects 0.000 description 37
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 34
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 34
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 34
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 33
- 239000000556 agonist Substances 0.000 description 32
- 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 29
- 125000000753 cycloalkyl group Chemical group 0.000 description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 26
- 238000011282 treatment Methods 0.000 description 26
- 102000023984 PPAR alpha Human genes 0.000 description 23
- 230000014509 gene expression Effects 0.000 description 22
- 208000019423 liver disease Diseases 0.000 description 21
- 230000002757 inflammatory effect Effects 0.000 description 20
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 20
- 210000001519 tissue Anatomy 0.000 description 19
- 108010035532 Collagen Proteins 0.000 description 18
- 102000008186 Collagen Human genes 0.000 description 18
- 229920001436 collagen Polymers 0.000 description 18
- 208000005069 pulmonary fibrosis Diseases 0.000 description 18
- 208000035475 disorder Diseases 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- 230000003510 anti-fibrotic effect Effects 0.000 description 16
- 108010028924 PPAR alpha Proteins 0.000 description 15
- 229910052805 deuterium Inorganic materials 0.000 description 15
- 125000004431 deuterium atom Chemical group 0.000 description 15
- 125000005843 halogen group Chemical group 0.000 description 15
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 230000001587 cholestatic effect Effects 0.000 description 14
- 230000001684 chronic effect Effects 0.000 description 14
- 230000002503 metabolic effect Effects 0.000 description 14
- 206010008635 Cholestasis Diseases 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 13
- 108010016731 PPAR gamma Proteins 0.000 description 13
- 102000000536 PPAR gamma Human genes 0.000 description 13
- 230000007870 cholestasis Effects 0.000 description 13
- 231100000359 cholestasis Toxicity 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 230000002195 synergetic effect Effects 0.000 description 13
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 12
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 12
- 210000003995 blood forming stem cell Anatomy 0.000 description 12
- 235000012000 cholesterol Nutrition 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 208000015181 infectious disease Diseases 0.000 description 12
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 12
- 208000015163 Biliary Tract disease Diseases 0.000 description 11
- 230000004913 activation Effects 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 10
- 125000000392 cycloalkenyl group Chemical group 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 208000011231 Crohn disease Diseases 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 8
- 206010009900 Colitis ulcerative Diseases 0.000 description 8
- FDTZUTSGGSRHQF-UHFFFAOYSA-N Desacetyl-nitazoxanide Chemical compound OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 FDTZUTSGGSRHQF-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 208000031886 HIV Infections Diseases 0.000 description 8
- 208000037357 HIV infectious disease Diseases 0.000 description 8
- 201000006704 Ulcerative Colitis Diseases 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 8
- 235000001014 amino acid Nutrition 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 8
- 239000012678 infectious agent Substances 0.000 description 8
- 239000011159 matrix material Substances 0.000 description 8
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 7
- 206010072877 Intestinal fibrosis Diseases 0.000 description 7
- 150000007942 carboxylates Chemical group 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 230000037406 food intake Effects 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- 206010010317 Congenital absence of bile ducts Diseases 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- 108010015181 PPAR delta Proteins 0.000 description 6
- 229940122054 Peroxisome proliferator-activated receptor delta agonist Drugs 0.000 description 6
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 6
- 208000012619 Progressive familial intrahepatic cholestasis type 3 Diseases 0.000 description 6
- UJTOVSZPBVTOMC-QKZHPOIUSA-N Tizoxanide glucuronide Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 UJTOVSZPBVTOMC-QKZHPOIUSA-N 0.000 description 6
- 201000005271 biliary atresia Diseases 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 229940125542 dual agonist Drugs 0.000 description 6
- 235000012631 food intake Nutrition 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 201000002148 progressive familial intrahepatic cholestasis 3 Diseases 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 5
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 5
- 108010082126 Alanine transaminase Proteins 0.000 description 5
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 5
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- 206010014561 Emphysema Diseases 0.000 description 5
- 101000637835 Homo sapiens Serum amyloid A-4 protein Proteins 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 5
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 5
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 5
- 206010039710 Scleroderma Diseases 0.000 description 5
- 102100032016 Serum amyloid A-4 protein Human genes 0.000 description 5
- 201000009594 Systemic Scleroderma Diseases 0.000 description 5
- 206010042953 Systemic sclerosis Diseases 0.000 description 5
- 208000036142 Viral infection Diseases 0.000 description 5
- 229960003767 alanine Drugs 0.000 description 5
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 5
- 208000006673 asthma Diseases 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 229940125753 fibrate Drugs 0.000 description 5
- 210000000987 immune system Anatomy 0.000 description 5
- 230000000968 intestinal effect Effects 0.000 description 5
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 206010028537 myelofibrosis Diseases 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 208000023504 respiratory system disease Diseases 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 230000009385 viral infection Effects 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 4
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 4
- 208000035143 Bacterial infection Diseases 0.000 description 4
- 206010004664 Biliary fibrosis Diseases 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 208000008964 Chemical and Drug Induced Liver Injury Diseases 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 206010072268 Drug-induced liver injury Diseases 0.000 description 4
- 208000032928 Dyslipidaemia Diseases 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 4
- 208000017170 Lipid metabolism disease Diseases 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 208000001145 Metabolic Syndrome Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 4
- 101710182361 Pyruvate:ferredoxin oxidoreductase Proteins 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- 206010050207 Skin fibrosis Diseases 0.000 description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 4
- 239000004473 Threonine Substances 0.000 description 4
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 4
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 235000009697 arginine Nutrition 0.000 description 4
- 229960001230 asparagine Drugs 0.000 description 4
- 235000009582 asparagine Nutrition 0.000 description 4
- 235000003704 aspartic acid Nutrition 0.000 description 4
- 208000022362 bacterial infectious disease Diseases 0.000 description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000112 colonic effect Effects 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- 239000000841 delta opiate receptor agonist Substances 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 208000016097 disease of metabolism Diseases 0.000 description 4
- 231100000594 drug induced liver disease Toxicity 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 206010017758 gastric cancer Diseases 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 235000004554 glutamine Nutrition 0.000 description 4
- 230000002440 hepatic effect Effects 0.000 description 4
- 210000004024 hepatic stellate cell Anatomy 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 4
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 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
- 229960000310 isoleucine Drugs 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 210000001370 mediastinum Anatomy 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 230000001613 neoplastic effect Effects 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 208000037803 restenosis Diseases 0.000 description 4
- 210000000574 retroperitoneal space Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 201000011549 stomach cancer Diseases 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 201000008827 tuberculosis Diseases 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010058029 Arthrofibrosis Diseases 0.000 description 3
- 208000033116 Asbestos intoxication Diseases 0.000 description 3
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- 208000024934 IgG4-related mediastinitis Diseases 0.000 description 3
- 208000014919 IgG4-related retroperitoneal fibrosis Diseases 0.000 description 3
- 208000002260 Keloid Diseases 0.000 description 3
- 208000002805 Mediastinal fibrosis Diseases 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 208000030852 Parasitic disease Diseases 0.000 description 3
- 206010034464 Periarthritis Diseases 0.000 description 3
- 206010036805 Progressive massive fibrosis Diseases 0.000 description 3
- 206010038979 Retroperitoneal fibrosis Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 3
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 description 3
- 208000010123 anthracosis Diseases 0.000 description 3
- 206010003441 asbestosis Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229960000516 bezafibrate Drugs 0.000 description 3
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 210000002808 connective tissue Anatomy 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
- 239000000890 drug combination Substances 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 229950001279 elafibranor Drugs 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 229960002591 hydroxyproline Drugs 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000001117 keloid Anatomy 0.000 description 3
- 210000003127 knee Anatomy 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 230000036281 parasite infection Effects 0.000 description 3
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 3
- 206010035653 pneumoconiosis Diseases 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 239000011885 synergistic combination Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 2
- IPBCWPPBAWQYOO-UHFFFAOYSA-N 2-(tetradecylthio)acetic acid Chemical compound CCCCCCCCCCCCCCSCC(O)=O IPBCWPPBAWQYOO-UHFFFAOYSA-N 0.000 description 2
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 2
- OQDQIFQRNZIEEJ-UHFFFAOYSA-N 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloroindol-2-yl]butanoic acid Chemical compound C1=C2N=CSC2=CC(S(=O)(=O)N2C3=CC=C(Cl)C=C3C=C2CCCC(=O)O)=C1 OQDQIFQRNZIEEJ-UHFFFAOYSA-N 0.000 description 2
- JBYXPOFIGCOSSB-GOJKSUSPSA-N 9-cis,11-trans-octadecadienoic acid Chemical compound CCCCCC\C=C\C=C/CCCCCCCC(O)=O JBYXPOFIGCOSSB-GOJKSUSPSA-N 0.000 description 2
- 206010054793 Arterial fibrosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- JHQXCEBEGVCTTB-UHFFFAOYSA-N CSc1ccc(cc1)C(=O)C=Cc1cc(C)c(C(O)=O)c(C)c1OC(C)C Chemical compound CSc1ccc(cc1)C(=O)C=Cc1cc(C)c(C(O)=O)c(C)c1OC(C)C JHQXCEBEGVCTTB-UHFFFAOYSA-N 0.000 description 2
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 2
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 239000004214 Fast Green FCF Substances 0.000 description 2
- RZSYLLSAWYUBPE-UHFFFAOYSA-L Fast green FCF Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC(O)=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 RZSYLLSAWYUBPE-UHFFFAOYSA-L 0.000 description 2
- HWVNEWGKWRGSRK-UHFFFAOYSA-N GW 0742 Chemical compound CC=1N=C(C=2C=C(F)C(=CC=2)C(F)(F)F)SC=1CSC1=CC=C(OCC(O)=O)C(C)=C1 HWVNEWGKWRGSRK-UHFFFAOYSA-N 0.000 description 2
- YDBLKRPLXZNVNB-UHFFFAOYSA-N GW 501516 Chemical compound CC=1N=C(C=2C=CC(=CC=2)C(F)(F)F)SC=1CSC1=CC=C(OCC(O)=O)C(C)=C1 YDBLKRPLXZNVNB-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 206010023330 Keloid scar Diseases 0.000 description 2
- 206010023421 Kidney fibrosis Diseases 0.000 description 2
- 229930195714 L-glutamate Natural products 0.000 description 2
- QNRRHYPPQFELSF-CNYIRLTGSA-N Laninamivir Chemical compound OC[C@@H](O)[C@@H](OC)[C@@H]1OC(C(O)=O)=C[C@H](N=C(N)N)[C@H]1NC(C)=O QNRRHYPPQFELSF-CNYIRLTGSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108010006035 Metalloproteases Proteins 0.000 description 2
- 102000005741 Metalloproteases Human genes 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010048654 Muscle fibrosis Diseases 0.000 description 2
- UOXSCWSIQODULA-UHFFFAOYSA-N NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)C(C)(C)C Chemical compound NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)C(C)(C)C UOXSCWSIQODULA-UHFFFAOYSA-N 0.000 description 2
- CDVOISDKGUFIOH-UHFFFAOYSA-N NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)[N+](=O)[O-])=O)C(C)(C)C Chemical compound NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)[N+](=O)[O-])=O)C(C)(C)C CDVOISDKGUFIOH-UHFFFAOYSA-N 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- UOXSCWSIQODULA-GFCCVEGCSA-N N[C@H](C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)C(C)(C)C Chemical compound N[C@H](C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)C(C)(C)C UOXSCWSIQODULA-GFCCVEGCSA-N 0.000 description 2
- 208000009905 Neurofibromatoses Diseases 0.000 description 2
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 2
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 206010051657 Ovarian fibrosis Diseases 0.000 description 2
- 108010044210 PPAR-beta Proteins 0.000 description 2
- 108010050808 Procollagen Proteins 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- YIQKLZYTHXTDDT-UHFFFAOYSA-H Sirius red F3B Chemical compound C1=CC(=CC=C1N=NC2=CC(=C(C=C2)N=NC3=C(C=C4C=C(C=CC4=C3[O-])NC(=O)NC5=CC6=CC(=C(C(=C6C=C5)[O-])N=NC7=C(C=C(C=C7)N=NC8=CC=C(C=C8)S(=O)(=O)[O-])S(=O)(=O)[O-])S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+] YIQKLZYTHXTDDT-UHFFFAOYSA-H 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 206010067269 Uterine fibrosis Diseases 0.000 description 2
- DBUQSBIXBUZXGQ-UTONKHPSSA-N [2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl] (2S)-2-amino-3,3-dimethylbutanoate hydrochloride Chemical compound Cl.CC(C)(C)[C@H](N)C(=O)Oc1ccccc1C(=O)Nc1ncc(s1)[N+]([O-])=O DBUQSBIXBUZXGQ-UTONKHPSSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000001919 adrenal effect Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 230000002141 anti-parasite Effects 0.000 description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000009787 cardiac fibrosis Effects 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000003167 cholangitis Diseases 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229940108924 conjugated linoleic acid Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 201000010048 endomyocardial fibrosis Diseases 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 235000019240 fast green FCF Nutrition 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- AFLFKFHDSCQHOL-IZZDOVSWSA-N gft505 Chemical compound C1=CC(SC)=CC=C1C(=O)\C=C\C1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1 AFLFKFHDSCQHOL-IZZDOVSWSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010562 histological examination Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 210000002510 keratinocyte Anatomy 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 208000008585 mastocytosis Diseases 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 230000002071 myeloproliferative effect Effects 0.000 description 2
- 210000000651 myofibroblast Anatomy 0.000 description 2
- 229950006238 nadide Drugs 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 201000004931 neurofibromatosis Diseases 0.000 description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 102000006255 nuclear receptors Human genes 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 201000002793 renal fibrosis Diseases 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 125000003375 sulfoxide group Chemical group 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002381 testicular Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- QINWTFKFPMRNJP-UHFFFAOYSA-N (2-chloro-4-nitrophenoxy)-ethyl-propan-2-yloxy-sulfanylidene-$l^{5}-phosphane Chemical compound CC(C)OP(=S)(CC)OC1=CC=C([N+]([O-])=O)C=C1Cl QINWTFKFPMRNJP-UHFFFAOYSA-N 0.000 description 1
- ZHKNLJLMDFQVHJ-RUZDIDTESA-N (2r)-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoic acid Chemical compound CC[C@H](C(O)=O)OC1=CC=CC(CN(CCCOC=2C=CC(OC)=CC=2)C=2OC3=CC=CC=C3N=2)=C1 ZHKNLJLMDFQVHJ-RUZDIDTESA-N 0.000 description 1
- QLJYLJGYIDIJPT-VIFPVBQESA-N (2s)-3-(4-aminophenyl)-2-methoxypropanoic acid Chemical compound CO[C@H](C(O)=O)CC1=CC=C(N)C=C1 QLJYLJGYIDIJPT-VIFPVBQESA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WLKCSMCLEKGITB-XWJJKCKWSA-N 15-HEPE Chemical compound CC\C=C/CC(O)\C=C\C=C/C\C=C/C\C=C/CCCC(O)=O WLKCSMCLEKGITB-XWJJKCKWSA-N 0.000 description 1
- NMRWDFUZLLQSBN-UHFFFAOYSA-N 2,4-dichloro-n-(3,5-dichloro-4-quinolin-3-yloxyphenyl)benzenesulfonamide Chemical compound ClC1=CC(Cl)=CC=C1S(=O)(=O)NC(C=C1Cl)=CC(Cl)=C1OC1=CN=C(C=CC=C2)C2=C1 NMRWDFUZLLQSBN-UHFFFAOYSA-N 0.000 description 1
- CKDHSXVPEJKVAJ-UHFFFAOYSA-N 2,6-dimethyl-4-[3-oxo-3-[4-(trifluoromethoxy)phenyl]prop-1-enyl]-3-propan-2-yloxybenzoic acid Chemical compound FC(OC1=CC=C(C=C1)C(C=CC1=C(C(=C(C(=C1)C)C(=O)O)C)OC(C)C)=O)(F)F CKDHSXVPEJKVAJ-UHFFFAOYSA-N 0.000 description 1
- MIBIHJTXYCJMMF-UHFFFAOYSA-N 2,6-dimethyl-4-[3-oxo-3-[4-(trifluoromethyl)phenyl]prop-1-enyl]-3-propan-2-yloxybenzoic acid Chemical compound FC(C1=CC=C(C=C1)C(C=CC1=C(C(=C(C(=C1)C)C(=O)O)C)OC(C)C)=O)(F)F MIBIHJTXYCJMMF-UHFFFAOYSA-N 0.000 description 1
- 239000003315 2-(4-chlorophenoxy)-2-methylpropanoic acid Substances 0.000 description 1
- GJQQFDFMSNAWEF-UHFFFAOYSA-N 2-[2,6-dimethyl-4-[3-(4-methylsulfanylphenyl)-3-oxopropyl]phenoxy]-2-methylpropanoic acid Chemical compound C1=CC(SC)=CC=C1C(=O)CCC1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1 GJQQFDFMSNAWEF-UHFFFAOYSA-N 0.000 description 1
- VYHYOBXBZHCQHS-UHFFFAOYSA-N 2-[2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 VYHYOBXBZHCQHS-UHFFFAOYSA-N 0.000 description 1
- GHCOJKMUTNVHCK-UHFFFAOYSA-N 2-[4-([1,3]dioxolo[4,5-f][1,3]benzothiazol-6-yl)-2-methylphenoxy]-2-methylpropanoic acid Chemical group C1=C(OC(C)(C)C(O)=O)C(C)=CC(C=2SC3=CC=4OCOC=4C=C3N=2)=C1 GHCOJKMUTNVHCK-UHFFFAOYSA-N 0.000 description 1
- JWHYSEDOYMYMNM-QGZVFWFLSA-N 2-[4-[(2r)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]sulfanyl-2-methylphenoxy]acetic acid Chemical compound C([C@@H](OCC)CSC=1C=C(C)C(OCC(O)=O)=CC=1)OC1=CC=C(C(F)(F)F)C=C1 JWHYSEDOYMYMNM-QGZVFWFLSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- UYGZODVVDUIDDQ-UHFFFAOYSA-N 3-[(2,4-dichlorophenyl)methyl]-2-methyl-n-pentylsulfonylbenzimidazole-5-carboxamide Chemical compound C12=CC(C(=O)NS(=O)(=O)CCCCC)=CC=C2N=C(C)N1CC1=CC=C(Cl)C=C1Cl UYGZODVVDUIDDQ-UHFFFAOYSA-N 0.000 description 1
- FTAGQROYQYQRHF-FCWZHQICSA-N 5-HEPE Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C=C/C(O)CCCC(O)=O FTAGQROYQYQRHF-FCWZHQICSA-N 0.000 description 1
- JCYNMRJCUYVDBC-UHFFFAOYSA-N 5-[[4-[[6-(4-amino-3,5-dimethylphenoxy)-1-methylbenzimidazol-2-yl]methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound CC1=C(N)C(C)=CC(OC=2C=C3N(C)C(COC=4C=CC(CC5C(NC(=O)S5)=O)=CC=4)=NC3=CC=2)=C1 JCYNMRJCUYVDBC-UHFFFAOYSA-N 0.000 description 1
- NLUNAYAEIJYXRB-VYOQERLCSA-N 8(S)-HETE Chemical compound CCCCC\C=C/C\C=C/C=C/[C@@H](O)C\C=C/CCCC(O)=O NLUNAYAEIJYXRB-VYOQERLCSA-N 0.000 description 1
- ZKRFOXLVOKTUTA-KQYNXXCUSA-N 9-(5-phosphoribofuranosyl)-6-mercaptopurine Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=S)=C2N=C1 ZKRFOXLVOKTUTA-KQYNXXCUSA-N 0.000 description 1
- 102000005606 Activins Human genes 0.000 description 1
- 201000011374 Alagille syndrome Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102100038495 Bile acid receptor Human genes 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- CDVOISDKGUFIOH-GFCCVEGCSA-N CC(C)(C)[C@H](N)C(=O)OC1=C(C=CC=C1)C(=O)NC1=NC=C(S1)[N+]([O-])=O Chemical compound CC(C)(C)[C@H](N)C(=O)OC1=C(C=CC=C1)C(=O)NC1=NC=C(S1)[N+]([O-])=O CDVOISDKGUFIOH-GFCCVEGCSA-N 0.000 description 1
- 101150083327 CCR2 gene Proteins 0.000 description 1
- 101150017501 CCR5 gene Proteins 0.000 description 1
- 101150072801 COL1A2 gene Proteins 0.000 description 1
- QDMONAIGPRKTII-UHFFFAOYSA-N CSc1ccc(cc1)C(=O)C=Cc1cc(C)c(C(=O)OC(C)C)c(C)c1OC(C)C Chemical compound CSc1ccc(cc1)C(=O)C=Cc1cc(C)c(C(=O)OC(C)C)c(C)c1OC(C)C QDMONAIGPRKTII-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- KPSRODZRAIWAKH-JTQLQIEISA-N Ciprofibrate Natural products C1=CC(OC(C)(C)C(O)=O)=CC=C1[C@H]1C(Cl)(Cl)C1 KPSRODZRAIWAKH-JTQLQIEISA-N 0.000 description 1
- BMOVQUBVGICXQN-UHFFFAOYSA-N Clinofibrate Chemical compound C1=CC(OC(C)(CC)C(O)=O)=CC=C1C1(C=2C=CC(OC(C)(CC)C(O)=O)=CC=2)CCCCC1 BMOVQUBVGICXQN-UHFFFAOYSA-N 0.000 description 1
- 241000223936 Cryptosporidium parvum Species 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 102000002148 Diacylglycerol O-acyltransferase Human genes 0.000 description 1
- 108010001348 Diacylglycerol O-acyltransferase Proteins 0.000 description 1
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 description 1
- 108050004099 Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 101150112014 Gapdh gene Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 101001018196 Homo sapiens Mitogen-activated protein kinase kinase kinase 5 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 229940126032 IVA-337 Drugs 0.000 description 1
- 102000005856 Inhibitory Smad Proteins Human genes 0.000 description 1
- 108010005239 Inhibitory Smad Proteins Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 201000005099 Langerhans cell histiocytosis Diseases 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 102000013460 Malate Dehydrogenase Human genes 0.000 description 1
- 108010026217 Malate Dehydrogenase Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 1
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 102100033127 Mitogen-activated protein kinase kinase kinase 5 Human genes 0.000 description 1
- 101150106019 Mmp2 gene Proteins 0.000 description 1
- 241000713869 Moloney murine leukemia virus Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- ZZIKIHCNFWXKDY-UHFFFAOYSA-N Myriocin Natural products CCCCCCC(=O)CCCCCCC=CCC(O)C(O)C(N)(CO)C(O)=O ZZIKIHCNFWXKDY-UHFFFAOYSA-N 0.000 description 1
- 108010002998 NADPH Oxidases Proteins 0.000 description 1
- 102000004722 NADPH Oxidases Human genes 0.000 description 1
- 238000013231 NASH rodent model Methods 0.000 description 1
- CHCSGBIMMOAKJS-UHFFFAOYSA-N NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)C(CC)C Chemical compound NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)C(CC)C CHCSGBIMMOAKJS-UHFFFAOYSA-N 0.000 description 1
- WOZVFXPPFKITEJ-UHFFFAOYSA-N NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)[N+](=O)[O-])=O)C(CC)C Chemical compound NC(C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)[N+](=O)[O-])=O)C(CC)C WOZVFXPPFKITEJ-UHFFFAOYSA-N 0.000 description 1
- CHCSGBIMMOAKJS-ZANVPECISA-N N[C@H](C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)[C@H](CC)C Chemical compound N[C@H](C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)Cl)=O)[C@H](CC)C CHCSGBIMMOAKJS-ZANVPECISA-N 0.000 description 1
- WOZVFXPPFKITEJ-ZANVPECISA-N N[C@H](C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)[N+](=O)[O-])=O)[C@H](CC)C Chemical compound N[C@H](C(=O)OC1=C(C=CC=C1)C(NC=1SC(=CN=1)[N+](=O)[O-])=O)[C@H](CC)C WOZVFXPPFKITEJ-ZANVPECISA-N 0.000 description 1
- 208000003510 Nephrogenic Fibrosing Dermopathy Diseases 0.000 description 1
- 206010067467 Nephrogenic systemic fibrosis Diseases 0.000 description 1
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 1
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 1
- 102100028448 Nuclear receptor subfamily 2 group C member 2 Human genes 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 229940124754 PPAR-alpha/gamma agonist Drugs 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102000002020 Protease-activated receptors Human genes 0.000 description 1
- 108050009310 Protease-activated receptors Proteins 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 101710141795 Ribonuclease inhibitor Proteins 0.000 description 1
- 229940122208 Ribonuclease inhibitor Drugs 0.000 description 1
- 102100037968 Ribonuclease inhibitor Human genes 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 241000405965 Scomberomorus brasiliensis Species 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 101710084188 TGF-beta receptor type-2 Proteins 0.000 description 1
- 102100033455 TGF-beta receptor type-2 Human genes 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 101150021063 Timp2 gene Proteins 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- JNSHUUGMOATZMV-NAWISMDQSA-N [2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl] (2S,3S)-2-amino-3-methylpentanoate hydrochloride Chemical compound Cl.CC[C@H](C)[C@H](N)C(=O)Oc1ccccc1C(=O)Nc1ncc(s1)[N+]([O-])=O JNSHUUGMOATZMV-NAWISMDQSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000011759 adipose tissue development Effects 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 229940054685 alinia Drugs 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 210000002469 basement membrane Anatomy 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
- 108091022863 bile acid binding Proteins 0.000 description 1
- 102000030904 bile acid binding Human genes 0.000 description 1
- 239000003858 bile acid conjugate Substances 0.000 description 1
- 229950004495 binifibrate Drugs 0.000 description 1
- BFYRHDVAEJIBON-UHFFFAOYSA-N binifibrate Chemical compound C=1C=CN=CC=1C(=O)OCC(COC(=O)C=1C=NC=CC=1)OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 BFYRHDVAEJIBON-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 235000020974 cholesterol intake Nutrition 0.000 description 1
- 201000010013 chronic cholangitis Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960002174 ciprofibrate Drugs 0.000 description 1
- KPSRODZRAIWAKH-UHFFFAOYSA-N ciprofibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C1C(Cl)(Cl)C1 KPSRODZRAIWAKH-UHFFFAOYSA-N 0.000 description 1
- 229950003072 clinofibrate Drugs 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229950008441 clofibric acid Drugs 0.000 description 1
- TXCGAZHTZHNUAI-UHFFFAOYSA-N clofibric acid Chemical compound OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 TXCGAZHTZHNUAI-UHFFFAOYSA-N 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 230000011382 collagen catabolic process Effects 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 229950002458 efatutazone Drugs 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- KYAKGJDISSNVPZ-UHFFFAOYSA-N etofylline clofibrate Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KYAKGJDISSNVPZ-UHFFFAOYSA-N 0.000 description 1
- 229950009036 etofylline clofibrate Drugs 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 210000002603 extrahepatic bile duct Anatomy 0.000 description 1
- 208000019298 familial intrahepatic cholestasis Diseases 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003352 fibrogenic effect Effects 0.000 description 1
- 229960000556 fingolimod Drugs 0.000 description 1
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 244000000013 helminth Species 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 210000003228 intrahepatic bile duct Anatomy 0.000 description 1
- 208000001024 intrahepatic cholestasis Diseases 0.000 description 1
- 230000007872 intrahepatic cholestasis Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 229940116871 l-lactate Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 230000004322 lipid homeostasis Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000004132 lipogenesis Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- XJHXZGHPCAKRFK-UHFFFAOYSA-N mbx-8025 Chemical compound CC1=NN(C=2C=CC(=CC=2)C(F)(F)F)N=C1CSC1=CC=C(OCC(O)=O)C(C)=C1 XJHXZGHPCAKRFK-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- IVAQJHSXBVHUQT-ZVHZXABRSA-N methyl (e)-3-(3,5-dimethoxyphenyl)-2-[4-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]phenyl]prop-2-enoate Chemical compound C=1C=C(OC=2C=CC(CC3C(NC(=O)S3)=O)=CC=2)C=CC=1/C(C(=O)OC)=C\C1=CC(OC)=CC(OC)=C1 IVAQJHSXBVHUQT-ZVHZXABRSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical class OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- ZZIKIHCNFWXKDY-GNTQXERDSA-N myriocin Chemical compound CCCCCCC(=O)CCCCCC\C=C\C[C@@H](O)[C@H](O)[C@@](N)(CO)C(O)=O ZZIKIHCNFWXKDY-GNTQXERDSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 229950005171 nicofibrate Drugs 0.000 description 1
- RARQHAFNGNPQCZ-UHFFFAOYSA-N nicofibrate Chemical compound C=1C=CN=CC=1COC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 RARQHAFNGNPQCZ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 230000008779 noncanonical pathway Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000006506 pH homeostasis Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000009996 pancreatic endocrine effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229950009401 pemafibrate Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000000858 peroxisomal effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NYZBXKOBOOCHFY-UHFFFAOYSA-N phenyl 2-amino-3,3-dimethylbutanoate Chemical compound CC(C)(C)C(N)C(=O)OC1=CC=CC=C1 NYZBXKOBOOCHFY-UHFFFAOYSA-N 0.000 description 1
- QKHIVXQAPKMQRV-UHFFFAOYSA-N phenyl 2-amino-3-methylpentanoate Chemical compound CCC(C)C(N)C(=O)OC1=CC=CC=C1 QKHIVXQAPKMQRV-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229950000957 pirifibrate Drugs 0.000 description 1
- YJBIJSVYPHRVCI-UHFFFAOYSA-N pirifibrate Chemical compound C=1C=CC(CO)=NC=1COC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 YJBIJSVYPHRVCI-UHFFFAOYSA-N 0.000 description 1
- 229950010439 plafibride Drugs 0.000 description 1
- DDDQVDIPBFGVIG-UHFFFAOYSA-N plafibride Chemical compound C1COCCN1CNC(=O)NC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 DDDQVDIPBFGVIG-UHFFFAOYSA-N 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 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
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- OBRIOHODJVKWGS-WSZABJOTSA-N potassium;(1r,5s)-2-hydroxy-3-(3-methylbutanoyl)-5-(3-methylbutyl)-1-(4-methylpentanoyl)-4-oxocyclopent-2-en-1-olate Chemical compound [K+].CC(C)CC[C@@H]1C(=O)C(C(=O)CC(C)C)=C(O)[C@@]1([O-])C(=O)CCC(C)C OBRIOHODJVKWGS-WSZABJOTSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- YOUSHMHNZRRNHF-UHFFFAOYSA-N propan-2-yl 2-[2,6-dimethyl-4-[3-(4-methylsulfanylphenyl)-3-oxopropyl]phenoxy]-2-methylpropanoate Chemical compound C1=CC(SC)=CC=C1C(=O)CCC1=CC(C)=C(OC(C)(C)C(=O)OC(C)C)C(C)=C1 YOUSHMHNZRRNHF-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229930182852 proteinogenic amino acid Natural products 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 239000003161 ribonuclease inhibitor Substances 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- MRWFZSLZNUJVQW-DEOSSOPVSA-N saroglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCN1C(C=2C=CC(SC)=CC=2)=CC=C1C MRWFZSLZNUJVQW-DEOSSOPVSA-N 0.000 description 1
- 229950006544 saroglitazar Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000008410 smoothened signaling pathway Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- VHLOANBRCFGJQF-UHFFFAOYSA-N tert-butyl 2,6-dimethyl-4-[3-(4-methylsulfanylphenyl)-3-oxoprop-1-enyl]-3-propan-2-yloxybenzoate Chemical compound CSC1=CC=C(C=C1)C(C=CC1=C(C(=C(C(=C1)C)C(=O)OC(C)(C)C)C)OC(C)C)=O VHLOANBRCFGJQF-UHFFFAOYSA-N 0.000 description 1
- ZYCGMEWAIXWTMF-UHFFFAOYSA-N tert-butyl 2,6-dimethyl-4-[3-oxo-3-[4-(trifluoromethoxy)phenyl]prop-1-enyl]-3-propan-2-yloxybenzoate Chemical compound CC(C)Oc1c(C)c(C(=O)OC(C)(C)C)c(C)cc1C=CC(=O)c1ccc(OC(F)(F)F)cc1 ZYCGMEWAIXWTMF-UHFFFAOYSA-N 0.000 description 1
- TXBJLAMSZFLJCY-UHFFFAOYSA-N tert-butyl 2,6-dimethyl-4-[3-oxo-3-[4-(trifluoromethyl)phenyl]prop-1-enyl]-3-propan-2-yloxybenzoate Chemical compound CC(C)Oc1c(C)c(C(=O)OC(C)(C)C)c(C)cc1C=CC(=O)c1ccc(cc1)C(F)(F)F TXBJLAMSZFLJCY-UHFFFAOYSA-N 0.000 description 1
- CXGTZJYQWSUFET-IBGZPJMESA-N tesaglitazar Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCC1=CC=C(OS(C)(=O)=O)C=C1 CXGTZJYQWSUFET-IBGZPJMESA-N 0.000 description 1
- 229950004704 tesaglitazar Drugs 0.000 description 1
- 108091008743 testicular receptors 4 Proteins 0.000 description 1
- 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 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- VPRFDABTJNLKKR-XHZSPPMBSA-N tocofibrate Chemical compound C([C@@](OC1=C(C)C=2C)(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC1=C(C)C=2OC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 VPRFDABTJNLKKR-XHZSPPMBSA-N 0.000 description 1
- 229950005856 tocofibrate Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000004061 uncoupling agent Substances 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
Description
(i)NTZ及びこの類似体から選択される化合物;並びに
(ii)少なくとも1つのPPARアゴニスト
を含む組合せ物に関する。
R1は、水素原子(H)、重水素原子(D)、ハロゲン原子、(C6~C14)アリール基、複素環基、(C3~C14)シクロアルキル基、(C1~C6)アルキル基、スルホニル基、スルホキシド基、(C1~C6)アルキルカルボニル基、(C1~C6)アルキルオキシ基、カルボキシル基、カルボキシレート基、ニトロ基(NO2)、アミノ基(NH2)、(C1~C6)アルキルアミノ基、アミド基、(C1~C6)アルキルアミド基、(C1~C6)ジアルキルアミド基を表し、
R2は、水素原子、重水素原子、NO2基、(C6~C14)アリール基、複素環基、ハロゲン原子、(C1~C6)アルキル基、(C3~C14)シクロアルキル基、(C2~C6)アルキニル基、(C1~C6)アルキルオキシ基、(C1~C6)アルキルチオ基、(C1~C6)アルキルカルボニル基、(C1~C6)アルキルカルボニルアミノ基、(C6~C14)アリールカルボニルアミノ基、カルボキシル若しくはカルボキシレート基、アミド基、(C1~C6)アルキルアミド基、(C1~C6)ジアルキルアミド基、NH2基、(C1~C6)アルキルアミノ基を表し、
又は
R1及びR2は、これらが結合している炭素原子と一緒に、置換若しくは非置換5~8員のシクロアルキル、複素環若しくはアリール基を形成し、
R3、R4、R5、R6及びR7は、同一であるか又は異なって、水素原子、重水素原子、ハロゲン原子、ヒドロキシル基、(C1~C6)アルキルカルボニル基、(C1~C6)アルキル基、(C1~C6)アルキルオキシ基、(C1~C6)アルキルチオ基、(C1~C6)アルキルカルボニルオキシ基、(C6~C14)アリールオキシ基、(C6~C14)アリール基、複素環基、(C3~C14)シクロアルキル基、NO2基、スルホニルアミノアルキル基、NH2基、アミノ(C1~C6)アルキル基、(C1~C6)アルキルカルボニルアミノ基、カルボキシル基、カルボキシレート基又はR9基を表し;
R9は、O-R8基、又はアミノ酸(該アミノ酸は、アラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、バリンからなる群から選択される。)、又は式(A):
(式中、R’は(C1~C6)アルキル基、(C2~C6)アルケニル基、(C2~C6)アルキニル基、(C3~C14)シクロアルキル基、(C3~C14)シクロアルキルアルキル基、(C3~C14)シクロアルキル(C2~C6)アルケニル基、(C3~C14)シクロアルケニル基、(C3~C14)シクロアルケニル(C1~C6)アルキル基、(C3~C14)シクロアルケニル(C2~C6)アルケニル基、(C3~C14)シクロアルケニル(C2~C6)アルキニル基を表し;
R”及びR”’は、独立して、水素原子、(C1~C6)アルキル基又は窒素保護基を表す。)
の部分を表し、
R8は、水素原子、重水素原子、グルクロニジル基又は
R1は、水素原子(H)、重水素原子(D)、ハロゲン原子、(C6~C14)アリール基、複素環基、(C3~C14)シクロアルキル基、(C1~C6)アルキル基、スルホニル基、スルホキシド基、(C1~C6)アルキルカルボニル基、(C1~C6)アルキルオキシ基、カルボキシル基、カルボキシレート基、NO2基、NH2基、(C1~C6)アルキルアミノ基、アミド基、(C1~C6)アルキルアミド基、(C1~C6)ジアルキルアミド基を表し、
R2は、水素原子、重水素原子、NO2基、(C6~C14)アリール基、複素環基、ハロゲン原子、(C1~C6)アルキル基、(C3~C14)シクロアルキル基、(C2~C6)アルキニル基、(C1~C6)アルキルオキシ基、(C1~C6)アルキルチオ基、(C1~C6)アルキルカルボニル基、(C1~C6)アルキルカルボニルアミノ基、(C6~C14)アリールカルボニルアミノ基、カルボキシル酸若しくはカルボキシレート基、アミド基、(C1~C6)アルキルアミド基、(C1~C6)ジアルキルアミド基、NH2基、(C1~C6)アルキルアミノ基を表し、
又は
R1及びR2は、これらが結合している炭素原子と一緒に、置換若しくは非置換5~8員のシクロアルキル、複素環若しくはアリール基を形成し、
R3は、水素原子、重水素原子、ハロゲン原子、O-R8基、(C1~C6)アルキルカルボニル基、(C1~C6)アルキル基、(C1~C6)アルキルオキシ基、(C1~C6)アルキルチオ基、(C1~C6)アルキルカルボニルオキシ基、(C6~C14)アリールオキシ基、(C6~C14)アリール基、複素環基、(C3~C14)シクロアルキル基、NO2、スルホニルアミノアルキル基、NH2基、アミノ(C1~C6)アルキル基、(C1~C6)アルキルカルボニルアミノ基、カルボキシル基、カルボキシレート基、アミノ酸(該アミノ酸は、アラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、バリンからなる群から選択される。)、又は式(A):
R”及びR”’は、独立して、水素原子、(C1~C6)アルキル基又は窒素保護基を表す。)
の部分を表し、R8は、水素原子、重水素原子、又は
R4、R5、R6及びR7は、同一であるか又は異なって、水素原子、重水素原子、ハロゲン原子、ヒドロキシル基、(C1~C6)アルキルカルボニル基、(C1~C6)アルキル基、(C1~C6)アルキルオキシ基、(C1~C6)アルキルチオ基、(C1~C6)アルキルカルボニルオキシ基、(C6~C14)アリールオキシ基、(C6~C14)アリール基、複素環基、(C3~C14)シクロアルキル基、NO2、スルホニルアミノ(C1~C6)アルキル基、NH2基、アミノ(C1~C6)アルキル基、(C1~C6)アルキルカルボニルアミノ基、カルボキシル基、カルボキシレート基、アミノ酸(該アミノ酸は、アラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、バリンからなる群から選択される。)、又は式(A):
の部分を表す。]
の化合物又は薬学的に許容されるその塩である。
(C1~C6)アルキル基は、置換又は非置換(C1~C6)アルキル基、特に置換又は非置換(C1~C4)アルキル基でもよく;
(C2~C6)アルキニル基は、置換又は非置換(C2~C6)アルキニル基でもよく;
(C3~C14)シクロアルキル基は、置換又は非置換(C3~C14)シクロアルキル基でもよく;
(C1~C6)アルキルオキシ基は、置換又は非置換(C1~C4)アルキルオキシ基のような置換又は非置換でもよく;
(C1~C6)アルキルチオ基は、置換又は非置換(C1~C4)アルキルチオ基のような置換又は非置換でもよく;
(C1~C6)アルキルアミノ基は、(C1~C4)アルキルアミノ基でもよく;
(C1~C6)ジアルキルアミノ基は、(C1~C4)ジアルキルアミノ基でもよく;
(C6~C14)アリール基は、置換又は非置換(C6~C14)アリール基でもよく;
複素環基は、置換又は非置換ヘテロシクロアルキル又はヘテロアリール基でもよい。
[式中、R9は、水素原子、重水素原子、O-R8基(R8は上で定義されているとおりである。)、又はアミノ酸(該アミノ酸は、アラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リジン、メチオニン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、バリンからなる群から選択される。)、又は式(A):
(式中、R’は、(C1~C6)アルキル基、(C2~C6)アルケニル基、(C2~C6)アルキニル基、(C3~C14)シクロアルキル基、(C3~C14)シクロアルキル(C1~C6)アルキル基、(C3~C14)シクロアルキル(C1~C6)アルケニル基、(C3~C14)シクロアルケニル基、(C3~C14)シクロアルケニル(C1~C6)アルキル基、(C3~C14)シクロアルケニル(C2~C6)アルケニル基、(C3~C14)シクロアルケニル(C2~C6)アルキニル基を表し;R”及びR”’は、独立して、水素原子、(C1~C6)アルキル基又は窒素保護基を表す。)
の部分を表す。]
の化合物である。
・NTZ:
[式中、
R8は、水素原子、重水素原子若しくは
R1、R2、R2a、R2b、R2c、R3、R4、R5及びR6は同時に水素原子ではないという条件で、R1、R3、R4、R5及びR6は、同一であるか若しくは異なって、水素原子若しくは重水素原子を表す。]
の化合物である。
・少なくとも1つのPPARアルファアゴニスト;
・少なくとも1つのPPARガンマアゴニスト;
・少なくとも1つのPPARデルタアゴニスト;
・少なくとも1つのPPARアルファ/デルタ二重アゴニスト;
・少なくとも1つのPPARアルファアゴニスト及び少なくとも1つのPPARデルタアゴニスト;
・少なくとも1つのPPARアルファ/ガンマ二重アゴニスト;
・少なくとも1つのPPARアルファアゴニスト及び少なくとも1つのPPARガンマアゴニスト;
・少なくとも1つのPPARガンマ/デルタ二重アゴニスト;
・少なくとも1つのPPARガンマアゴニスト及び少なくとも1つのPPARデルタアゴニスト;
・少なくとも1つのPPARアルファ/ガンマ/デルタ パンアゴニスト;並びに
・少なくとも1つのPPARアルファアゴニスト、少なくとも1つのPPARガンマアゴニスト及び少なくとも1つのPPARデルタアゴニスト
である。
[式中、Y1はハロゲン、Ra又はGa-Ra基を表し;
AはCH=CH又はCH2-CH2基を表し;
Y2はGb-Rb基を表し;
Ga及びGbは、同一であるか又は異なって、酸素又は硫黄の原子を表し;
Raは、水素原子、非置換(C1~C6)アルキル基、(C6~C14)アリール基又は1つ以上のハロゲン原子、(C1~C6)アルコキシ又は(C1~C6)アルキルチオ基により置換されている(C1~C6)アルキル基、(C3~C14)シクロアルキル基、(C3~C14)シクロアルキルチオ基又は複素環基を表し;
Rbは、少なくとも-COORc基により置換されている(C1~C6)アルキル基を表し、ここで、Rcは水素原子、又は1つ以上のハロゲン原子により置換されているか若しくは置換されていない(C1~C6)アルキル基、(C3~C14)シクロアルキル基又は複素環基を表し;並びに
Y4及びY5は、同一であるか又は異なって、1つ以上のハロゲン原子により置換されているか若しくは置換されていない(C1~C6)アルキル基、(C3~C14)シクロアルキル基又は複素環基を表す。]
の化合物、又は薬学的に許容されるその塩である。
Y1はハロゲン、Ra又はGa-Ra基を表し;
AはCH=CH基を表し;
Y2はGb-Rb基を表し;
Ga及びGbは、同一であるか又は異なって、酸素又は硫黄の原子を表し;
Raは、(C1~C6)アルキル又は(C3~C14)シクロアルキル基、特に1つ以上のハロゲン原子により置換されているか若しくは置換されていない(C1~C7)アルキル又は(C3~C14)シクロアルキル基を表し;
Rbは、-COOR3基により置換されている(C1~C6)アルキル基を表し、ここで、Rcは水素原子又は1~4炭素原子を有するアルキル基を表し;並びに
Y4及びY5は、独立して(C1~C4)アルキル基を表す。
Y1はRa又はGa-Ra基を表し;
AはCH2-CH2基を表し;
Y2はGb-Rb基を表し;
Gaは酸素又は硫黄の原子を表し、Gbは酸素原子を表し;
Raは、(C1~C6)アルキル又は(C3~C7)シクロアルキル基を表し;
Rbは、少なくとも-COORc基により置換されている(C1~C6)アルキル基を表し、ここで、Rcは水素原子又は(C1~C4)アルキル基を表し;並びに
Y4及びY5は、独立して(C1~C4)アルキル基を表す。
Y1はハロゲン原子又はRa若しくはGa-Ra基を表し;
AはCH2-CH2基を表し;
Y2はGb-Rb基を表し;
Gaは酸素又は硫黄の原子を表し、Gbは酸素原子を表し;
Raは、1つ以上のハロゲン原子で置換されている(C1~C6)アルキル又は(C3~C14)シクロアルキル基を表し;
Rbは、1つ以上のハロゲン原子により置換されているか又は置換されていない及び少なくとも-COORc基により置換されている(C1~C6)アルキル基を表し、ここで、Rcは水素原子又は(C1~C4)アルキル基を表し;並びに
Y4及びY5は(C1~C4)アルキル基を表す。
・成分(ii)はエラフィブラノール、サログリタザル、セラデルパル及びラニフィブラノールからなる群において選択され、成分(ii)はより詳細にはエラフィブラノールであり;
・成分(i)はNTZ、TZ、2-[(5-ニトロ-1,3-チアゾール-2-イル)カルバモイル]フェニル(d3)エタノエート、2-[(5-ニトロ-1,3-チアゾール-2-イル)カルバモイル]フェニル(d2)エタノエート、2-[(5-ニトロ-1,3-チアゾール-2-イル)カルバモイル]フェニル(d1)エタノエート、((S)-2-(5-ニトロチアゾール-2-イルカルバモイル)フェニル 2-アミノ-3,3-ジメチルブタノエート塩酸塩)又は((2S,3S)-2-(5-ニトロチアゾール-2-イルカルバモイル)フェニル 2-アミノ-3-メチルペンタノエート塩酸塩)から選択される。
AP-1 活性化タンパク質
ASBTi アピカルナトリウム共依存性胆汁酸トランスポーター阻害剤
ASK1 シグナル調節キナーゼ1
AT1 アンジオテンシン1
COPD 慢性閉塞性肺疾患
CTGF 結合組織成長因子
DGAT ジアシルグリセロール-O-アシルトランスフェラーゼ
DMSO ジメチルスルホキシド
DNA デオキシリボ核酸
DPP4 ジペプチジルペプチダーゼ
ELISA 酵素結合免疫アッセイ
EOB エクセスオーバーブリス
FABAC 脂肪酸胆汁酸コンジュゲート
FBS ウシ胎仔血清
FGF 線維芽細胞成長因子
FXR ファルネソイドX受容体
GDF 増殖分化因子
GLP-1 グルカゴン様ペプチド-1
GPCR Gタンパク質共役型受容体
HBV B型肝炎ウイルス
HCV C型肝炎ウイルス
15-HEPE 5-ヒドロキシエイコサペンタエン酸
HIV ヒト免疫不全ウイルス
HSC 肝星細胞
IC50 50%阻害濃度
iNOS 誘導型一酸化窒素合成酵素
IPF 特発性肺性線維症
LANI ラニフィブラノール
LBD リガンド結合ドメイン
LPS リポ多糖
LT ロイコトリエン
MAPK マイトジェン活性化プロテインキナーゼ
MMP-9 メタロプロテアーゼ9
MMPase メタロプロテアーゼ
NADPH ニコチンアミドアデニンジヌクレオチドリン酸
NAFLD 非アルコール性脂肪性肝疾患
NASH 非アルコール性脂肪性肝炎
NF-κB 核内因子カッパB
NOX NADPHオキシダーゼ
NSAIDs 非ステロイド性抗炎症剤
NTZ ニタゾキサニド
PAR プロテアーゼ活性化受容体
PBC 原発性胆汁性胆管炎
PDE ホスホジエステラーゼ
PDGF 血小板由来成長因子
PFIC3 家族性肝内胆汁うっ滞型3
PFOR ピルベート:フェレドキシン酸化還元酵素
PPAR ペルオキシソーム増殖因子活性化受容体
PPRE PPAR応答エレメント
PSC 原発性硬化性胆管炎
ROCK Rho関連タンパク質キナーゼ
RTK 受容体チロシンキナーゼ
SARO サログリタザル
SD 標準偏差
SELA セラデルパル
SGLT ナトリウムグルコース輸送
STAT 転写のシグナルトランスデューサー及び活性化因子
TGFβ 形質転換成長因子β
TGFBRI TGFβ受容体I型
TGFBRII TGFβ受容体II型
THBS1 トロンボスポンジン1
THRβ 甲状腺受容体β
TIMP メタロプロテアーゼの組織阻害剤
TLR-4 Toll様受容体4
TZ チゾキサニド
TZG チゾキサニドグルクロニド
VAP-1 血管接着タンパク質-1
化合物はジメチルスルホキシド(DMSO、Fluka カタログ番号41640)に溶解させた。ニタゾキサニド(INTERCHIM カタログ番号RQ550U)、チゾキサニド(INTERCHIM カタログ番号RP253)、ラニフィブラノール(ARK PHARM カタログ番号AK689102)、セラデルパル(ARK PHARM カタログ番号AK689146)及びサログリタザル(CHEMEXPRESS カタログ番号YY-1997A)は市販のものを入手した。
ヒト始原肝星細胞(hHSC)(innoprot)を、2%ウシ胎仔血清(FBS、ScienCell カタログ番号0010)、1%ペニシリン/ストレプトマイシン(ScienCell カタログ番号0503)及び星細胞成長補助剤(SteCGS;ScienCell カタログ番号5352)を補充したSTeCM培地(ScienCell カタログ番号5301)で培養した。細胞培養フラスコは、接着をよくするためにポリ-L-リジン(Sigma カタログ番号P4707)で被覆した。
2成分組合せマトリックス(NTZ/エラフィブラノール)
これらの実験では、チェッカーボードマトリックスを作成した。NTZ及びエラフィブラノールストックは、96ウェルプレート又は384ウェルプレートの横の列(PPARアゴニストエラフィブラノール)の5ポイントシリーズで、及び縦の列NTZ)の6ポイントシリーズでDMSOに連続希釈した。その後、5×6組合せマトリックスを、すべての単剤濃度の1対1混合により作成した。化合物ごとの試験濃度は、TGF-β1で刺激されたHSCモデルにおいてα-SMA含有量を測定することにより得られる単剤としてそれぞれの化合物のそれぞれのIC50に基づいて選んだ。
ヒト始原肝星細胞(hHSC)(innoprot)を上記の通りに、標準条件下で培養した。それに続いて細胞を、ELISAによるα-SMAの測定のために、96ウェルプレートに2×104細胞/ウェル及び384ウェルプレートに6500細胞/ウェルの密度で蒔いた。次の日、細胞培養培地を取り除き、細胞はリン酸緩衝食塩水(PBS)(Invitrogen カタログ番号14190)で洗浄した。hHSCは、無血清及びSteCGS無し培地で24時間欠乏させた。
α-SMAのレベルはサンドイッチELISAを使用して測定した。手短に述べれば、ELISAプレートのウェルにまず4℃で一晩捕捉抗体(マウスモノクローナル抗ACTA2、Abnova)で被覆した。PBS+0.2%のTween20で3回洗浄した後、PBS+0.2%のBSAからなるブロッキング液を添加して1時間置き、次にさらに洗浄サイクルにかけた。細胞可溶化物は、室温で2時間の期間、捕捉抗体への結合のためにウェルに移した。洗浄手順後、検出抗体(ビオチン化マウスモノクローナル抗ACTA2、Abnova)を室温で添加して2時間置き、続いて3回洗浄した。検出では、HRPコンジュゲートストレプトアビジン(R&R System カタログ番号DY998)をまず室温で30分間適用させた。洗浄後、HRP基質TMB(BD、番号555214)を添加し、室温暗所で7分間インキュベートした。酸化させると、TMBは水溶性の青色反応生成物を形成し、これは硫酸の添加で黄色になり(溶解停止)、分光光度計を使用する450nmでの強度の正確な測定が可能になる。発色は溶解物中に存在するα-SMAの量に正比例する。
αSMA ELISAアッセイで得られた値は、まずTGF-β1対照に対するパーセント阻害に変換した。次に、これらのパーセント阻害を使用して、EOB(エクセスオーバーブリス)を決定して薬剤組合せの相乗効果を明確にした。予測されるブリスアディティビズムスコアー(E)は第一に式:
E=(A+B)-(A×B)により決定し、A及びBは所与の用量でのNTZ(A)及びエラフィブラノール、サログリタザル、セラデルパル又はラニフィブラノール(B)のパーセント阻害である。同じ用量での組合せNTZ/エラフィブラノール、サログリタザル、セラデルパル又はラニフィブラノールのブリス予測と観測された阻害の差は「エクセスオーバーブリス」スコアーである。
・エクセスオーバーブリススコアー>0は、相加的よりも大きな活性を示している(相乗的);及び
・エクセスオーバーブリススコアー<0は、組合せが相加的よりも低いことを示している(拮抗的)。
組合せNTZ+エラフィブラノールでは、付加的な全ブリススコアーはすべてのEOBの合計により計算した。
実験設計
コリン欠乏及びLアミノ酸限定(CDAA)食はコリンを欠き、コリンは肝臓β酸化及び極めて低密度のリポタンパク質産生に不可欠であり、肝細胞を誘導して脂肪を貯蔵させその後細胞損傷を引き起こすと考えられている。CDAA食誘発性齧歯類モデルは比較的短期間内に線維症を発症し、NASH病理、特に線維症の可逆性を迅速に研究するのに理想的である。
一部のマウスにはCDAAc食を与えた。
一部のマウスにはエラフィブラノール1又は3mg/kg/日を補充したCDAAc食を与えた。
一部のマウスにはNTZ30又は100mg/kg/日を補充したCDAAc食を与えた。
一部のマウスにはエラフィブラノールとNTZ組合せを異なる比:1+30、1+100、3+30及び3+100mg/kg/日で補充したCDAAc食を与えた。
・餌摂取量は、グラム餌/グラム動物/日で表される
・餌中0.02%のニタゾキサニド
○0.02gのcpd/100gの餌=0.2mgのcpd/gの餌
・cpdの実際の用量:
○0.2mgのcpd/グラム餌/グラム動物/日
○(0.2mgのcpd/グラム餌/グラム動物/日)×1000=(0.2mgのcpd/グラム餌/kgの動物/日)=200mgのcpd/グラム餌/kgの動物/日
したがって、グラム餌/グラム動物/日で表される餌摂取量値に200を掛ける;得られた値は、mgのNTZ/kgの動物/日で表される実際の投与用量に一致する。
・NTZ0.00667%wt/wtの用量では、実際の処置用量は餌摂取量値(グラム餌/グラム動物/日)に66.7を掛けることにより得られた。
アラニンアミノトランスフェラーゼ(ALT)
ALTの血漿濃度は、Daytona automateの適切なRandoxキット(Randox、カタログ番号AL3801)を使用して決定した。手短に述べれば、血漿試料内のALTは、αオキソグルタル酸及びL-アラニンをL-グルタミン酸塩及びピルベートに酵素的に変換する。NADHの存在下で、生成したピルベートは乳酸デヒドロゲナーゼにより転換されてL-乳酸塩及びNAD+を形成する。反応の動態学は研究されており、ALTの血漿レベルを計算することができる。結果はU/Lで表される。
ASTの血漿濃度は、Daytona automateの適切なRandoxキット(Randox、カタログ番号AS3804)を使用して決定した。手短に述べれば、血漿試料内のASTは、αオキソグルタル酸塩及びL-アスパラギン酸塩をL-グルタミン酸塩及びオキサロ酢酸塩に酵素的に変換する。NADHの存在下で、生成したオキサロ酢酸塩はリンゴ酸デヒドロゲナーゼにより転換されてL-リンゴ酸塩及びNAD+を形成する。反応の動態学は研究されており、ASTの血漿レベルを計算することができる。結果はU/Lで表される。
屠殺時、肝臓試料は組織学的分析のために処理され、以下の通りに試験した。
肝臓切片は先ずホルマリン4%液中12時間固定した。次に、肝臓片はPBSで30分間洗浄し、エタノール液(70、80、95及び100%エタノールの連続浴槽)中で脱水した。肝臓片はキシレンの3つの異なる浴槽(Sigma-Aldrich、カタログ番号534056)、続いて液体パラフィン(60℃)の2つの浴槽でインキュベートした。次に、肝臓片はHistowax(登録商標)で穏やかに満たされたラック中に入れ組織を完全に覆った。
肝臓切片は脱パラフィンし、再水和し、0.5%酢酸(Sigma-Aldrich、カタログ番号695092)の浴槽ですすぐ前にFast Green FCF0.04%(Sigma-Aldrich、カタログ番号F7258)の溶液中15分間インキュベートした。次に、肝臓切片は水ですすぎ、飽和水性ピクリン酸(Sigma-Aldrich、カタログ番号P6744)中Fast Green FCF0.04%~0.1%シリウスレッド(Direct Red80、Fluka カタログ番号43665)の溶液中30分間インキュベートした。次に切片は脱水し、CV Mount培地(Leica、カタログ番号14046430011)を使用してマウントした。
それぞれの肝臓検体の供給源に盲検の専門家が組織学的検査を実施した。バーチャルスライドは、3D HistechからPannoramic 250スキャナーを使用して作成した。Quant Centerソフトウェア(Pattern Quant及びHisto Quantモジュールを含む、3D Histech)を使用して、コラーゲン染色域を定量化した。手短に述べれば、Pattern Quantを使用して組織を検出し、その表面を測定した。次に、Histo Quantを使用して、色閾値法に基づいて、染色コラーゲン含有量を検出しその表面を測定した。次に線維症域は、動物ごとの全組織に対するコラーゲン表面のパーセントとして表した。
実験結果は平均±標準偏差(SD)として表され、棒グラフ又は曲線としてプロットした。統計解析は、Prismバージョン7を使用して以下の通りに実施した。屠殺後に実施した測定では、CSAA対CDAA+1%コレステロール群を、スチューデントt検定(#:p<0.05;##:<0.01;###:p<0.001)により又はマンホイットニー検定($:p<0.05;$$:<0.01;$$$:p<0.001)により比較した。処置群は、一元配置分散分析及び未修正フィッシャーLSD事後によりCDAA+1%コレステロール食と比較した(*:p<0.05;**p<0.01;***p<0.001)。
肝臓コラーゲン含有量は適切なQuickZymeキット(Total collagen assay、カタログ番号QZB-totcol5)を使用して決定した。アッセイはヒドロキシプロリンの検出に基づいており、これはコラーゲンの三重螺旋体で主に見出される非タンパク質原性アミノ酸である。したがって、組織加水分解物中のヒドロキシプロリンは、組織に存在するコラーゲンの量の直接の尺度として使用することが可能である(プロコラーゲン、成熟コラーゲン及びコラーゲン分解産物の区別はない)。
PIIINPの血漿濃度は、Cloud-Clone Corp社製のELISAアッセイ(カタログ番号SEA573Ra)を製造業者の説明書に従って使用して決定した。マイクロタイタープレートにPIIINPに特異的な抗体をプレコートする。標準又は試料を、PIIINPに特異的なビオチンコンジュゲート抗体と一緒に適切なマイクロタイタープレートウェルに添加する。次に、西洋ワサビペルオキシダーゼ(HRP)にコンジュゲートしたアビジンをそれぞれのマイクロプレートウェルに添加しインキュベートする。TMB基質溶液を添加した後、PIIINP、ビオチンコンジュゲート抗体及び酵素コンジュゲートアビジンを含有するウェルのみが色の変化を示す。酵素基質反応は硫酸溶液の添加により終了させ、色の変化は450nm±10nmの波長で分光光度的に測定する。次に試料中のPIIINPの濃度は、試料のODを標準曲線と比較することにより決定する。結果はpg/mLで表される。
RNA抽出
肝臓全RNAは、Nucleospin(登録商標)96キット(Macherey Nagel)を製造業者の説明書に従って使用して単離した。150ngの全RNAは、RTバッファー1×(Invitrogen カタログ番号P/NY02321)、1mMのDTT(Invitrogen カタログ番号P/NY00147)、0.5mMのdNTP(Promega)、200ng pdN6(Roche カタログ番号11034731001)及び40Uのリボヌクレアーゼ阻害剤(Promega カタログ番号N2515)の存在下、M-MLV-RT(モロニーマウス白血病ウイルス逆転写酵素)(Invitrogen カタログ番号28025)を使用してcDNAに逆転写した。
分化した筋線維芽細胞の異常な持続性は多くの線維性疾患の特徴である。
Claims (8)
- 線維性疾患を治療するための方法において使用するための組合せ物であって、
(i)ニタゾキサニドから選択される化合物又は薬学的に許容されるその塩;並びに
(ii)エラフィブラノール、セラデルパル、サログリタザル及びラニフィブラノールからなる群から選択される少なくとも1つのPPARアゴニスト又は薬学的に許容されるその塩
を含む、組合せ物。 - (i)ニタゾキサニドから選択される化合物又は薬学的に許容されるその塩;並びに
(ii)エラフィブラノール若しくは薬学的に許容されるその塩
を含む、請求項1に記載の組合せ物。 - 前記組合せ物が、成分i)及びii)、並びに薬学的に許容される担体を含む組成物である、請求項1又は2に記載の組合せ物。
- 線維性疾患を治療するための方法において、成分i)及びii)が、連続、分離又は同時使用される、請求項1~3のいずれか一項に記載の組合せ物。
- ピルフェニドン、受容体チロシンキナーゼ阻害剤(RTKI)、アンジオテンシンII(AT1)受容体遮断薬、CTGF阻害剤、潜伏性TGFβ複合体の活性化剤、及びTGFβ受容体I型(TGFBRI)若しくはII型(TGFBII)又はそれらのリガンドから選択される少なくとも1つの治療的活性剤をさらに含む、請求項1~4のいずれか一項に記載の組合せ物。
- さらなる治療的活性剤が、ピルフェニドン、ニンテダニブ、ソラフェニブ、MMP2、MMP9、THBS1、細胞表面インテグリン、TGFβ、アクチビン、インヒビン、Nodal、抗ミューラー管ホルモン、GDF及びBMPから選択される、請求項5に記載の組合せ物。
- 成分(i)及び(ii)が、持効性及び/又は徐放性放出のために、注射可能な懸濁液、ジェル、オイル、ピル、錠剤、坐薬、粉末、カプセル、エアロゾル、軟膏、クリーム、パッチ、又はガレヌス形態の手段で製剤化される、請求項1~6のいずれか一項に記載の組合せ物。
- 線維性疾患が、肝臓、腎臓、皮膚、表皮、内皮、筋肉、腱、軟骨、心臓、膵臓、肺、子宮、神経系、精巣、卵巣、副腎、動脈、静脈、結腸、腸、胆道、軟部組織、骨髄、関節及び胃線維症からなる群において選択される、請求項1~7のいずれか一項に記載の使用のための組合せ物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17305094 | 2017-01-27 | ||
EP17305094.9 | 2017-01-27 | ||
EP17305268.9 | 2017-03-13 | ||
EP17305268 | 2017-03-13 | ||
EP17190723.1 | 2017-09-12 | ||
EP17190723 | 2017-09-12 | ||
PCT/EP2018/052159 WO2018138352A1 (en) | 2017-01-27 | 2018-01-29 | Pharmaceutical compositions for combination therapy |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020506920A JP2020506920A (ja) | 2020-03-05 |
JP7224294B2 true JP7224294B2 (ja) | 2023-02-17 |
Family
ID=61157183
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019541179A Active JP7224294B2 (ja) | 2017-01-27 | 2018-01-29 | 組合せ療法のための医薬組成物 |
Country Status (15)
Country | Link |
---|---|
US (2) | US11033534B2 (ja) |
EP (1) | EP3573614A1 (ja) |
JP (1) | JP7224294B2 (ja) |
KR (1) | KR102537043B1 (ja) |
CN (1) | CN110198708B (ja) |
AU (1) | AU2018212614B2 (ja) |
BR (1) | BR112019015406A2 (ja) |
CA (1) | CA3046158A1 (ja) |
CO (1) | CO2019008103A2 (ja) |
IL (1) | IL267703B (ja) |
MX (1) | MX2019008917A (ja) |
PH (1) | PH12019501301A1 (ja) |
SG (1) | SG11201906041QA (ja) |
WO (1) | WO2018138352A1 (ja) |
ZA (1) | ZA201905510B (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA201991990A1 (ru) * | 2017-02-24 | 2020-04-07 | Женфит | Фармацевтические композиции для комбинированной терапии |
CN110025621A (zh) * | 2019-03-13 | 2019-07-19 | 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) | 替唑尼特和硝唑尼特在制备抗炎药物中的应用 |
CA3130713A1 (en) * | 2019-04-09 | 2020-10-15 | Peggy Parroche | Combination of nitazoxanide and elafibranor for the treatment of immune diseases or inflammation |
BR112021020496A2 (pt) * | 2019-04-12 | 2021-12-07 | Genfit | Nitazoxanida e tiazolidas para uso no tratamento de doenças associadas ao estresse oxidativo |
KR102199640B1 (ko) * | 2020-01-06 | 2021-01-07 | 브렉소젠 주식회사 | 라니피브라노르를 포함하는 줄기세포 유래 엑소좀 생성 촉진 및 줄기세포기능 강화용 조성물 |
US20220401420A1 (en) * | 2019-10-28 | 2022-12-22 | Genfit | Combination therapy having antioxydant properties |
US11478533B2 (en) | 2020-04-27 | 2022-10-25 | Novo Nordisk A/S | Semaglutide for use in medicine |
WO2022051323A1 (en) * | 2020-09-03 | 2022-03-10 | Coherus Biosciences, Inc. | Fixed dose combinations of chs-131 and a ppar agonist |
CN114044761B (zh) * | 2021-02-24 | 2022-05-17 | 成都贝诺科成生物科技有限公司 | 一种新的硝基噻唑衍生物及其应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009522371A (ja) | 2006-01-09 | 2009-06-11 | ロマーク ラボラトリーズ エル.シー. | ウイルス性肝炎の処置 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1437800A (en) | 1973-08-08 | 1976-06-03 | Phavic Sprl | Derivatives of 2-benzamido-5-nitro-thiazoles |
US8785442B2 (en) * | 2011-01-30 | 2014-07-22 | Curegenix, Inc. | Compound as antagonist of lysophosphatidic acid receptor, composition, and use thereof |
EA201391262A1 (ru) | 2011-03-02 | 2014-03-31 | Джером Шентаг | Композиция, способ лечения и диагностики стеатоза печени как самостоятельного заболевания или в комбинации с инфекцией гепатита с |
-
2018
- 2018-01-29 BR BR112019015406A patent/BR112019015406A2/pt active Search and Examination
- 2018-01-29 CA CA3046158A patent/CA3046158A1/en active Pending
- 2018-01-29 MX MX2019008917A patent/MX2019008917A/es unknown
- 2018-01-29 KR KR1020197024250A patent/KR102537043B1/ko active IP Right Grant
- 2018-01-29 CN CN201880008087.3A patent/CN110198708B/zh active Active
- 2018-01-29 AU AU2018212614A patent/AU2018212614B2/en active Active
- 2018-01-29 EP EP18702961.6A patent/EP3573614A1/en active Pending
- 2018-01-29 US US16/479,382 patent/US11033534B2/en active Active
- 2018-01-29 SG SG11201906041QA patent/SG11201906041QA/en unknown
- 2018-01-29 JP JP2019541179A patent/JP7224294B2/ja active Active
- 2018-01-29 WO PCT/EP2018/052159 patent/WO2018138352A1/en active Application Filing
-
2019
- 2019-06-10 PH PH12019501301A patent/PH12019501301A1/en unknown
- 2019-06-27 IL IL267703A patent/IL267703B/en unknown
- 2019-07-26 CO CONC2019/0008103A patent/CO2019008103A2/es unknown
- 2019-08-21 ZA ZA2019/05510A patent/ZA201905510B/en unknown
-
2021
- 2021-05-10 US US17/316,115 patent/US12053456B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009522371A (ja) | 2006-01-09 | 2009-06-11 | ロマーク ラボラトリーズ エル.シー. | ウイルス性肝炎の処置 |
Non-Patent Citations (1)
Title |
---|
Gastroenterology,2016年,150,pp.1147-1159 |
Also Published As
Publication number | Publication date |
---|---|
IL267703B (en) | 2022-05-01 |
US11033534B2 (en) | 2021-06-15 |
PH12019501301A1 (en) | 2019-12-11 |
US12053456B2 (en) | 2024-08-06 |
AU2018212614A1 (en) | 2019-06-27 |
MX2019008917A (es) | 2019-12-09 |
ZA201905510B (en) | 2023-03-29 |
BR112019015406A2 (pt) | 2020-05-19 |
US20210275504A1 (en) | 2021-09-09 |
WO2018138352A1 (en) | 2018-08-02 |
EP3573614A1 (en) | 2019-12-04 |
CO2019008103A2 (es) | 2019-08-20 |
CA3046158A1 (en) | 2018-08-02 |
AU2018212614B2 (en) | 2024-02-01 |
KR102537043B1 (ko) | 2023-05-25 |
US20190388398A1 (en) | 2019-12-26 |
SG11201906041QA (en) | 2019-08-27 |
KR20190108141A (ko) | 2019-09-23 |
CN110198708B (zh) | 2022-09-20 |
JP2020506920A (ja) | 2020-03-05 |
IL267703A (en) | 2019-08-29 |
CN110198708A (zh) | 2019-09-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7224294B2 (ja) | 組合せ療法のための医薬組成物 | |
US11191749B2 (en) | Pharmaceutical compositions for combination therapy | |
JP7266530B2 (ja) | エラフィブラノールのようなPPARアゴニスト及びアセチルCoAカルボキシラーゼ(ACC)を含む組合せ | |
AU2018223146B2 (en) | Combination of a PPAR agonist with a FXR agonist | |
KR102633249B1 (ko) | 조합 치료를 위한 약학 조성물 | |
TW202135812A (zh) | 使用整聯蛋白抑制劑組合治療肝臟疾病 | |
EA042720B1 (ru) | Фармацевтический комбинированный продукт и его применение в качестве лекарственного средства | |
EA044654B1 (ru) | Фармацевтический комбинированный продукт и его применение | |
EA044618B1 (ru) | Комбинированный продукт для лечения фиброзного или холестатического заболевания | |
EA042734B1 (ru) | КОМБИНАЦИЯ, СОДЕРЖАЩАЯ ТАКОЙ АГОНИСТ PPAR, КАК ЭЛАФИБРАНОР И ИНГИБИТОР АЦЕТИЛ-КоА-КАРБОКСИЛАЗЫ (АКК) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210107 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20211029 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20211102 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220127 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220502 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20220802 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221202 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20221202 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20221222 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20230110 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230124 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230207 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7224294 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |