CN112334137A - 用于nash和其他代谢紊乱的孤儿核受体调节剂 - Google Patents
用于nash和其他代谢紊乱的孤儿核受体调节剂 Download PDFInfo
- Publication number
- CN112334137A CN112334137A CN201980044009.3A CN201980044009A CN112334137A CN 112334137 A CN112334137 A CN 112334137A CN 201980044009 A CN201980044009 A CN 201980044009A CN 112334137 A CN112334137 A CN 112334137A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- agonists
- inhibitors
- receptor
- 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.)
- Pending
Links
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 title claims abstract description 56
- 208000030159 metabolic disease Diseases 0.000 title claims abstract description 12
- 102000004164 orphan nuclear receptors Human genes 0.000 title description 2
- 108090000629 orphan nuclear receptors Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 177
- 102000005962 receptors Human genes 0.000 claims abstract description 146
- 108020003175 receptors Proteins 0.000 claims abstract description 146
- 238000000034 method Methods 0.000 claims abstract description 124
- 239000000203 mixture Substances 0.000 claims abstract description 91
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 35
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000019423 liver disease Diseases 0.000 claims abstract description 12
- 102000016978 Orphan receptors Human genes 0.000 claims abstract description 6
- 108070000031 Orphan receptors Proteins 0.000 claims abstract description 6
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims abstract description 5
- 229930002330 retinoic acid Natural products 0.000 claims abstract description 5
- 229960001727 tretinoin Drugs 0.000 claims abstract description 5
- 208000026278 immune system disease Diseases 0.000 claims abstract description 4
- 208000015114 central nervous system disease Diseases 0.000 claims abstract 5
- -1 C3-10Cycloalkyl radical Chemical class 0.000 claims description 91
- 239000000556 agonist Substances 0.000 claims description 86
- 210000004185 liver Anatomy 0.000 claims description 82
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 63
- 239000003112 inhibitor Substances 0.000 claims description 57
- 229940002612 prodrug Drugs 0.000 claims description 54
- 239000000651 prodrug Substances 0.000 claims description 54
- 239000002105 nanoparticle Substances 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 230000014509 gene expression Effects 0.000 claims description 42
- 239000003814 drug Substances 0.000 claims description 41
- 239000005557 antagonist Substances 0.000 claims description 40
- 230000015572 biosynthetic process Effects 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 37
- 102000007399 Nuclear hormone receptor Human genes 0.000 claims description 36
- 108020005497 Nuclear hormone receptor Proteins 0.000 claims description 36
- 238000009472 formulation Methods 0.000 claims description 33
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Substances 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 claims description 30
- 239000013543 active substance Substances 0.000 claims description 29
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 28
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 24
- 241000282414 Homo sapiens Species 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 150000002632 lipids Chemical class 0.000 claims description 20
- 150000004712 monophosphates Chemical class 0.000 claims description 19
- 229910019142 PO4 Inorganic materials 0.000 claims description 18
- 239000012190 activator Substances 0.000 claims description 18
- 201000011510 cancer Diseases 0.000 claims description 18
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 18
- 239000000194 fatty acid Substances 0.000 claims description 18
- 229930195729 fatty acid Natural products 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 150000003254 radicals Chemical class 0.000 claims description 18
- 125000004122 cyclic group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 239000010452 phosphate Substances 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 235000021317 phosphate Nutrition 0.000 claims description 16
- 229940125396 insulin Drugs 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 102000004877 Insulin Human genes 0.000 claims description 13
- 108090001061 Insulin Proteins 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 13
- 206010022489 Insulin Resistance Diseases 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 229940107161 cholesterol Drugs 0.000 claims description 12
- 150000004665 fatty acids Chemical class 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 12
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 230000004060 metabolic process Effects 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 235000012000 cholesterol Nutrition 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- 108010011459 Exenatide Proteins 0.000 claims description 9
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 9
- 208000008589 Obesity Diseases 0.000 claims description 9
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 9
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 9
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 235000020824 obesity Nutrition 0.000 claims description 9
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 9
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 claims description 8
- 102100027840 Acyl-CoA wax alcohol acyltransferase 1 Human genes 0.000 claims description 8
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 8
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 8
- 101000698136 Homo sapiens Acyl-CoA wax alcohol acyltransferase 1 Proteins 0.000 claims description 8
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 8
- 150000001412 amines Chemical group 0.000 claims description 8
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 7
- 230000003178 anti-diabetic effect Effects 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229960001519 exenatide Drugs 0.000 claims description 7
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 7
- 229960001381 glipizide Drugs 0.000 claims description 7
- 239000004031 partial agonist Substances 0.000 claims description 7
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 7
- 102100039164 Acetyl-CoA carboxylase 1 Human genes 0.000 claims description 6
- 102100022089 Acyl-[acyl-carrier-protein] hydrolase Human genes 0.000 claims description 6
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 claims description 6
- 102100038495 Bile acid receptor Human genes 0.000 claims description 6
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 6
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 6
- 108010018763 Biotin carboxylase Proteins 0.000 claims description 6
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 claims description 6
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 claims description 6
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 claims description 6
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 claims description 6
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 claims description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 6
- 108010039731 Fatty Acid Synthases Proteins 0.000 claims description 6
- 102000000393 Ghrelin Receptors Human genes 0.000 claims description 6
- 108010016122 Ghrelin Receptors Proteins 0.000 claims description 6
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 claims description 6
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 6
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 claims description 6
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 6
- 108010019598 Liraglutide Proteins 0.000 claims description 6
- 102400001132 Melanin-concentrating hormone Human genes 0.000 claims description 6
- 101800002739 Melanin-concentrating hormone Proteins 0.000 claims description 6
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 claims description 6
- 102000015494 Mitochondrial Uncoupling Proteins Human genes 0.000 claims description 6
- 108010050258 Mitochondrial Uncoupling Proteins Proteins 0.000 claims description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 6
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 6
- 208000026594 alcoholic fatty liver disease Diseases 0.000 claims description 6
- 239000000883 anti-obesity agent Substances 0.000 claims description 6
- 239000003472 antidiabetic agent Substances 0.000 claims description 6
- 229940125710 antiobesity agent Drugs 0.000 claims description 6
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 6
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 229960002701 liraglutide Drugs 0.000 claims description 6
- 102000004311 liver X receptors Human genes 0.000 claims description 6
- 108090000865 liver X receptors Proteins 0.000 claims description 6
- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 claims description 6
- 229960003105 metformin Drugs 0.000 claims description 6
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 5
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 claims description 5
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 claims description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 5
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 claims description 5
- 108090001005 Interleukin-6 Proteins 0.000 claims description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 5
- 229940100389 Sulfonylurea Drugs 0.000 claims description 5
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 5
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 claims description 5
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 5
- 229960004166 diltiazem Drugs 0.000 claims description 5
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 230000009977 dual effect Effects 0.000 claims description 5
- 229960004580 glibenclamide Drugs 0.000 claims description 5
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 150000003626 triacylglycerols Chemical class 0.000 claims description 5
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 108010078791 Carrier Proteins Proteins 0.000 claims description 4
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 claims description 4
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 claims description 4
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 claims description 4
- 108010023302 HDL Cholesterol Proteins 0.000 claims description 4
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- XVVOERDUTLJJHN-UHFFFAOYSA-N Lixisenatide Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(N)=O)C(=O)NCC(=O)NCC(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N1C(CCC1)C(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)CC)NC(=O)C(NC(=O)C(CC(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCSC)NC(=O)C(CCC(N)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC=1C=CC=CC=1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)CNC(=O)C(N)CC=1NC=NC=1)C(C)O)C(C)O)C(C)C)CC1=CC=CC=C1 XVVOERDUTLJJHN-UHFFFAOYSA-N 0.000 claims description 4
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims description 4
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims description 4
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 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 claims description 4
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 4
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 235000006708 antioxidants Nutrition 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 102000012740 beta Adrenergic Receptors Human genes 0.000 claims description 4
- 108010079452 beta Adrenergic Receptors Proteins 0.000 claims description 4
- 229960000517 boceprevir Drugs 0.000 claims description 4
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 claims description 4
- 230000001906 cholesterol absorption Effects 0.000 claims description 4
- 239000001177 diphosphate Substances 0.000 claims description 4
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 4
- 235000011180 diphosphates Nutrition 0.000 claims description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 claims description 4
- 239000005556 hormone Substances 0.000 claims description 4
- 108010004367 lixisenatide Proteins 0.000 claims description 4
- 229950004994 meglitinide Drugs 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 229960000698 nateglinide Drugs 0.000 claims description 4
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 claims description 4
- 229960003512 nicotinic acid Drugs 0.000 claims description 4
- 235000001968 nicotinic acid Nutrition 0.000 claims description 4
- 239000011664 nicotinic acid Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 4
- TZIRZGBAFTZREM-MKAGXXMWSA-N pramlintide Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)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]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H]1NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)CSSC1)[C@@H](C)O)C(C)C)C1=CC=CC=C1 TZIRZGBAFTZREM-MKAGXXMWSA-N 0.000 claims description 4
- 108010029667 pramlintide Proteins 0.000 claims description 4
- 229960002354 repaglinide Drugs 0.000 claims description 4
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 claims description 4
- 229960003250 telithromycin Drugs 0.000 claims description 4
- 150000001467 thiazolidinediones Chemical class 0.000 claims description 4
- 235000011178 triphosphate Nutrition 0.000 claims description 4
- 239000001226 triphosphate Substances 0.000 claims description 4
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 3
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 3
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 3
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 3
- 102100027499 5-hydroxytryptamine receptor 1B Human genes 0.000 claims description 3
- 101710138639 5-hydroxytryptamine receptor 1B Proteins 0.000 claims description 3
- 239000005541 ACE inhibitor Substances 0.000 claims description 3
- 108010006533 ATP-Binding Cassette Transporters Proteins 0.000 claims description 3
- 102000005416 ATP-Binding Cassette Transporters Human genes 0.000 claims description 3
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 claims description 3
- PTQXTEKSNBVPQJ-UHFFFAOYSA-N Avasimibe Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1CC(=O)NS(=O)(=O)OC1=C(C(C)C)C=CC=C1C(C)C PTQXTEKSNBVPQJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940122361 Bisphosphonate Drugs 0.000 claims description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 3
- 101710150887 Cholecystokinin A Proteins 0.000 claims description 3
- 102000016862 Dicarboxylic Acid Transporters Human genes 0.000 claims description 3
- 108010092943 Dicarboxylic Acid Transporters Proteins 0.000 claims description 3
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 claims description 3
- 102400001370 Galanin Human genes 0.000 claims description 3
- 101800002068 Galanin Proteins 0.000 claims description 3
- 229940122904 Glucagon receptor antagonist Drugs 0.000 claims description 3
- 102000030595 Glucokinase Human genes 0.000 claims description 3
- 108010021582 Glucokinase Proteins 0.000 claims description 3
- 108091052347 Glucose transporter family Proteins 0.000 claims description 3
- 108010051696 Growth Hormone Proteins 0.000 claims description 3
- 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 claims description 3
- 206010056328 Hepatic ischaemia Diseases 0.000 claims description 3
- 102000000543 Histamine Receptors Human genes 0.000 claims description 3
- 108010002059 Histamine Receptors Proteins 0.000 claims description 3
- 108010065920 Insulin Lispro Proteins 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 108010008364 Melanocortins Proteins 0.000 claims description 3
- 102400000740 Melanocyte-stimulating hormone alpha Human genes 0.000 claims description 3
- 101710151321 Melanostatin Proteins 0.000 claims description 3
- 101710200814 Melanotropin alpha Proteins 0.000 claims description 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 3
- 101150027439 NPY1 gene Proteins 0.000 claims description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 3
- 102400000064 Neuropeptide Y Human genes 0.000 claims description 3
- 102000002512 Orexin Human genes 0.000 claims description 3
- 102000023984 PPAR alpha Human genes 0.000 claims description 3
- 108010028924 PPAR alpha Proteins 0.000 claims description 3
- 229920012196 Polyoxymethylene Copolymer Polymers 0.000 claims description 3
- 108010069820 Pro-Opiomelanocortin Proteins 0.000 claims description 3
- 102100027467 Pro-opiomelanocortin Human genes 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010063837 Reperfusion injury Diseases 0.000 claims description 3
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 3
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 claims description 3
- 102100038803 Somatotropin Human genes 0.000 claims description 3
- 229940123237 Taxane Drugs 0.000 claims description 3
- 229940122388 Thrombin inhibitor Drugs 0.000 claims description 3
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 claims description 3
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 3
- 229930003779 Vitamin B12 Natural products 0.000 claims description 3
- 239000000013 adrenergic uptake inhibitor Substances 0.000 claims description 3
- 101150115889 al gene Proteins 0.000 claims description 3
- DAYKLWSKQJBGCS-NRFANRHFSA-N aleglitazar Chemical compound C1=2C=CSC=2C(C[C@H](OC)C(O)=O)=CC=C1OCCC(=C(O1)C)N=C1C1=CC=CC=C1 DAYKLWSKQJBGCS-NRFANRHFSA-N 0.000 claims description 3
- 229950010157 aleglitazar Drugs 0.000 claims description 3
- 229960005260 amiodarone Drugs 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 229940127218 antiplatelet drug Drugs 0.000 claims description 3
- 230000003143 atherosclerotic effect Effects 0.000 claims description 3
- 229950010046 avasimibe Drugs 0.000 claims description 3
- 229940125388 beta agonist Drugs 0.000 claims description 3
- 239000002876 beta blocker Substances 0.000 claims description 3
- 239000003613 bile acid Substances 0.000 claims description 3
- 239000003858 bile acid conjugate Substances 0.000 claims description 3
- 229920000080 bile acid sequestrant Polymers 0.000 claims description 3
- 239000000480 calcium channel blocker Substances 0.000 claims description 3
- QEVLNUAVAONTEW-UZYHXJQGSA-L calcium;(2s)-4-[(3as,7ar)-1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl]-2-benzyl-4-oxobutanoate;dihydrate Chemical compound O.O.[Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 QEVLNUAVAONTEW-UZYHXJQGSA-L 0.000 claims description 3
- 229930003827 cannabinoid Natural products 0.000 claims description 3
- 239000003557 cannabinoid Substances 0.000 claims description 3
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 3
- 229960005091 chloramphenicol Drugs 0.000 claims description 3
- 230000001587 cholestatic effect Effects 0.000 claims description 3
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims description 3
- 229960001380 cimetidine Drugs 0.000 claims description 3
- 229960003405 ciprofloxacin Drugs 0.000 claims description 3
- 230000007882 cirrhosis Effects 0.000 claims description 3
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 3
- 229960002626 clarithromycin Drugs 0.000 claims description 3
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 claims description 3
- 229960001214 clofibrate Drugs 0.000 claims description 3
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 claims description 3
- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 claims description 3
- 229960002402 cobicistat Drugs 0.000 claims description 3
- 229960005319 delavirdine Drugs 0.000 claims description 3
- 229940116901 diethyldithiocarbamate Drugs 0.000 claims description 3
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 claims description 3
- 230000003511 endothelial effect Effects 0.000 claims description 3
- 229960003276 erythromycin Drugs 0.000 claims description 3
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims description 3
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 3
- 229960004884 fluconazole Drugs 0.000 claims description 3
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 3
- 229960004038 fluvoxamine Drugs 0.000 claims description 3
- 229960000304 folic acid Drugs 0.000 claims description 3
- 235000019152 folic acid Nutrition 0.000 claims description 3
- 239000011724 folic acid Substances 0.000 claims description 3
- SIGSPDASOTUPFS-XUDSTZEESA-N gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 claims description 3
- 229960005352 gestodene Drugs 0.000 claims description 3
- 239000003862 glucocorticoid Substances 0.000 claims description 3
- 239000003635 glucocorticoid antagonist Substances 0.000 claims description 3
- 239000000122 growth hormone Substances 0.000 claims description 3
- 229960002897 heparin Drugs 0.000 claims description 3
- 229920000669 heparin Polymers 0.000 claims description 3
- 229960001340 histamine Drugs 0.000 claims description 3
- 230000007412 host metabolism Effects 0.000 claims description 3
- HPMRFMKYPGXPEP-UHFFFAOYSA-N idazoxan Chemical compound N1CCN=C1C1OC2=CC=CC=C2OC1 HPMRFMKYPGXPEP-UHFFFAOYSA-N 0.000 claims description 3
- 229950001476 idazoxan Drugs 0.000 claims description 3
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 3
- 229960002411 imatinib Drugs 0.000 claims description 3
- 230000001506 immunosuppresive effect Effects 0.000 claims description 3
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 claims description 3
- 229960001936 indinavir Drugs 0.000 claims description 3
- 229960004130 itraconazole Drugs 0.000 claims description 3
- 229960004125 ketoconazole Drugs 0.000 claims description 3
- 229960004844 lovastatin Drugs 0.000 claims description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 3
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002865 melanocortin Substances 0.000 claims description 3
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 claims description 3
- 229960003248 mifepristone Drugs 0.000 claims description 3
- 229960003365 mitiglinide Drugs 0.000 claims description 3
- SLZIZIJTGAYEKK-CIJSCKBQSA-N molport-023-220-247 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CNC=N1 SLZIZIJTGAYEKK-CIJSCKBQSA-N 0.000 claims description 3
- 239000003887 narcotic antagonist Substances 0.000 claims description 3
- VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical compound O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 claims description 3
- 229960001800 nefazodone Drugs 0.000 claims description 3
- 229960003966 nicotinamide Drugs 0.000 claims description 3
- 235000005152 nicotinamide Nutrition 0.000 claims description 3
- 239000011570 nicotinamide Substances 0.000 claims description 3
- 229960002748 norepinephrine Drugs 0.000 claims description 3
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 3
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 3
- 229960001180 norfloxacin Drugs 0.000 claims description 3
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 claims description 3
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 claims description 3
- 229960001601 obeticholic acid Drugs 0.000 claims description 3
- 108060005714 orexin Proteins 0.000 claims description 3
- 239000000419 plant extract Substances 0.000 claims description 3
- 239000000106 platelet aggregation inhibitor Substances 0.000 claims description 3
- 150000003058 platinum compounds Chemical group 0.000 claims description 3
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 3
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 3
- 229960000311 ritonavir Drugs 0.000 claims description 3
- 229960001852 saquinavir Drugs 0.000 claims description 3
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 229940095743 selective estrogen receptor modulator Drugs 0.000 claims description 3
- 239000000333 selective estrogen receptor modulator Substances 0.000 claims description 3
- 230000003637 steroidlike Effects 0.000 claims description 3
- WRGVLTAWMNZWGT-VQSPYGJZSA-N taspoglutide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NC(C)(C)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)C(C)(C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 WRGVLTAWMNZWGT-VQSPYGJZSA-N 0.000 claims description 3
- 229950007151 taspoglutide Drugs 0.000 claims description 3
- 239000003868 thrombin inhibitor Substances 0.000 claims description 3
- 108090000721 thyroid hormone receptors Proteins 0.000 claims description 3
- 102000004217 thyroid hormone receptors Human genes 0.000 claims description 3
- 229960004394 topiramate Drugs 0.000 claims description 3
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 3
- 229960001641 troglitazone Drugs 0.000 claims description 3
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 claims description 3
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 claims description 3
- 229960001722 verapamil Drugs 0.000 claims description 3
- 229940088594 vitamin Drugs 0.000 claims description 3
- 229930003231 vitamin Natural products 0.000 claims description 3
- 235000013343 vitamin Nutrition 0.000 claims description 3
- 239000011782 vitamin Substances 0.000 claims description 3
- 235000019163 vitamin B12 Nutrition 0.000 claims description 3
- 239000011715 vitamin B12 Substances 0.000 claims description 3
- 235000019158 vitamin B6 Nutrition 0.000 claims description 3
- 239000011726 vitamin B6 Substances 0.000 claims description 3
- 229940011671 vitamin b6 Drugs 0.000 claims description 3
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 claims description 3
- RZPAXNJLEKLXNO-UHFFFAOYSA-N (20R,22R)-3beta,22-Dihydroxylcholest-5-en Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C(O)CCC(C)C)C1(C)CC2 RZPAXNJLEKLXNO-UHFFFAOYSA-N 0.000 claims description 2
- RZPAXNJLEKLXNO-GFKLAVDKSA-N (22R)-22-hydroxycholesterol 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)[C@H](O)CCC(C)C)[C@@]1(C)CC2 RZPAXNJLEKLXNO-GFKLAVDKSA-N 0.000 claims description 2
- IOWMKBFJCNLRTC-XWXSNNQWSA-N (24S)-24-hydroxycholesterol 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)CC[C@H](O)C(C)C)[C@@]1(C)CC2 IOWMKBFJCNLRTC-XWXSNNQWSA-N 0.000 claims description 2
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 2
- MSFZPBXAGPYVFD-NFBCFJMWSA-N (2r)-2-amino-3-[1-[3-[2-[2-[2-[4-[[(5s)-5,6-diamino-6-oxohexyl]amino]butylamino]-2-oxoethoxy]ethoxy]ethylamino]-3-oxopropyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid Chemical compound NC(=O)[C@@H](N)CCCCNCCCCNC(=O)COCCOCCNC(=O)CCN1C(=O)CC(SC[C@H](N)C(O)=O)C1=O MSFZPBXAGPYVFD-NFBCFJMWSA-N 0.000 claims description 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 2
- GVIYUKXRXPXMQM-BPXGDYAESA-N 221231-10-3 Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CSSC1)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(C)C)=O)C1=CC=C(O)C=C1 GVIYUKXRXPXMQM-BPXGDYAESA-N 0.000 claims description 2
- IOWMKBFJCNLRTC-UHFFFAOYSA-N 24S-hydroxycholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(O)C(C)C)C1(C)CC2 IOWMKBFJCNLRTC-UHFFFAOYSA-N 0.000 claims description 2
- 108010070305 AOD 9604 Proteins 0.000 claims description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
- 208000019901 Anxiety disease Diseases 0.000 claims description 2
- 200000000007 Arterial disease Diseases 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 2
- 229940123208 Biguanide Drugs 0.000 claims description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 2
- 102000011727 Caspases Human genes 0.000 claims description 2
- 108010076667 Caspases Proteins 0.000 claims description 2
- 229920001268 Cholestyramine Polymers 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 208000015943 Coeliac disease Diseases 0.000 claims description 2
- 229920002911 Colestipol Polymers 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 claims description 2
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 239000004131 EU approved raising agent Substances 0.000 claims description 2
- 108010061435 Enalapril Proteins 0.000 claims description 2
- NAXSRXHZFIBFMI-UHFFFAOYSA-N GW 3965 Chemical compound OC(=O)CC1=CC=CC(OCCCN(CC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC=2C(=C(C=CC=2)C(F)(F)F)Cl)=C1 NAXSRXHZFIBFMI-UHFFFAOYSA-N 0.000 claims description 2
- 101800001586 Ghrelin Proteins 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 102400000324 Glucagon-like peptide 1(7-37) Human genes 0.000 claims description 2
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 claims description 2
- 102000003886 Glycoproteins Human genes 0.000 claims description 2
- 108090000288 Glycoproteins Proteins 0.000 claims description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 2
- 229940122199 Insulin secretagogue Drugs 0.000 claims description 2
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 2
- 208000011200 Kawasaki disease Diseases 0.000 claims description 2
- 108010028554 LDL Cholesterol Proteins 0.000 claims description 2
- 238000008214 LDL Cholesterol Methods 0.000 claims description 2
- 102000016267 Leptin Human genes 0.000 claims description 2
- 108010092277 Leptin Proteins 0.000 claims description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 2
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 2
- 208000031845 Pernicious anaemia Diseases 0.000 claims description 2
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 claims description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 206010037549 Purpura Diseases 0.000 claims description 2
- 241001672981 Purpura Species 0.000 claims description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 2
- 206010039710 Scleroderma Diseases 0.000 claims description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 2
- 102000005782 Squalene Monooxygenase Human genes 0.000 claims description 2
- 108020003891 Squalene monooxygenase Proteins 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 229930003427 Vitamin E Natural products 0.000 claims description 2
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 claims description 2
- 229960002632 acarbose Drugs 0.000 claims description 2
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 claims description 2
- 208000024340 acute graft versus host disease Diseases 0.000 claims description 2
- 239000000670 adrenergic alpha-2 receptor antagonist Substances 0.000 claims description 2
- 229960004733 albiglutide Drugs 0.000 claims description 2
- OGWAVGNOAMXIIM-UHFFFAOYSA-N albiglutide Chemical compound O=C(O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)CNC(=O)C(NC(=O)CNC(=O)C(N)CC=1(N=CNC=1))CCC(=O)O)C(O)C)CC2(=CC=CC=C2))C(O)C)CO)CC(=O)O)C(C)C)CO)CO)CC3(=CC=C(O)C=C3))CC(C)C)CCC(=O)O)CCC(=O)N)C)C)CCCCN)CCC(=O)O)CC4(=CC=CC=C4))C(CC)C)C)CC=6(C5(=C(C=CC=C5)NC=6)))CC(C)C)C(C)C)CCCCN)CCCNC(=N)N OGWAVGNOAMXIIM-UHFFFAOYSA-N 0.000 claims description 2
- 229960004343 alendronic acid Drugs 0.000 claims description 2
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 claims description 2
- 229960001667 alogliptin Drugs 0.000 claims description 2
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 claims description 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
- MZZLGJHLQGUVPN-HAWMADMCSA-N anacetrapib Chemical compound COC1=CC(F)=C(C(C)C)C=C1C1=CC=C(C(F)(F)F)C=C1CN1C(=O)O[C@H](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)[C@@H]1C MZZLGJHLQGUVPN-HAWMADMCSA-N 0.000 claims description 2
- 229950000285 anacetrapib Drugs 0.000 claims description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 2
- 239000003957 anion exchange resin Substances 0.000 claims description 2
- 208000007474 aortic aneurysm Diseases 0.000 claims description 2
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 claims description 2
- 229960003856 argatroban Drugs 0.000 claims description 2
- 208000028922 artery disease Diseases 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 208000010668 atopic eczema Diseases 0.000 claims description 2
- 229960005370 atorvastatin Drugs 0.000 claims description 2
- 235000013734 beta-carotene Nutrition 0.000 claims description 2
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 claims description 2
- 239000011648 beta-carotene Substances 0.000 claims description 2
- 229960002747 betacarotene Drugs 0.000 claims description 2
- 150000004283 biguanides Chemical class 0.000 claims description 2
- 229940096699 bile acid sequestrants Drugs 0.000 claims description 2
- 229960004111 buformin Drugs 0.000 claims description 2
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 claims description 2
- 229940084891 byetta Drugs 0.000 claims description 2
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 2
- 229960000830 captopril Drugs 0.000 claims description 2
- 229960000590 celecoxib Drugs 0.000 claims description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 2
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 claims description 2
- 229960005110 cerivastatin Drugs 0.000 claims description 2
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 claims description 2
- 201000001883 cholelithiasis Diseases 0.000 claims description 2
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 claims description 2
- 208000017760 chronic graft versus host disease Diseases 0.000 claims description 2
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 claims description 2
- 229960002604 colestipol Drugs 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 claims description 2
- 229960003850 dabigatran Drugs 0.000 claims description 2
- 229960003834 dapagliflozin Drugs 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 229960003638 dopamine Drugs 0.000 claims description 2
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 2
- 229960000873 enalapril Drugs 0.000 claims description 2
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 claims description 2
- 229950010170 epalrestat Drugs 0.000 claims description 2
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 claims description 2
- 230000036566 epidermal hyperplasia Effects 0.000 claims description 2
- 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 claims description 2
- 229960002297 fenofibrate Drugs 0.000 claims description 2
- 239000002319 fibrinogen receptor antagonist Substances 0.000 claims description 2
- 229960003765 fluvastatin Drugs 0.000 claims description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 claims description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 claims description 2
- 229960004346 glimepiride Drugs 0.000 claims description 2
- 108010063245 glucagon-like peptide 1 (7-36)amide Proteins 0.000 claims description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 239000000859 incretin Substances 0.000 claims description 2
- 229940125425 inverse agonist Drugs 0.000 claims description 2
- 229960002198 irbesartan Drugs 0.000 claims description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 2
- 229940039781 leptin Drugs 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 229960001093 lixisenatide Drugs 0.000 claims description 2
- 229960004773 losartan Drugs 0.000 claims description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims description 2
- 229960004329 metformin hydrochloride Drugs 0.000 claims description 2
- 201000000626 mucocutaneous leishmaniasis Diseases 0.000 claims description 2
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 claims description 2
- 206010028417 myasthenia gravis Diseases 0.000 claims description 2
- SGIWFELWJPNFDH-UHFFFAOYSA-N n-(2,2,2-trifluoroethyl)-n-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}benzenesulfonamide Chemical compound C1=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=C1N(CC(F)(F)F)S(=O)(=O)C1=CC=CC=C1 SGIWFELWJPNFDH-UHFFFAOYSA-N 0.000 claims description 2
- 229940053128 nerve growth factor Drugs 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 229940121308 nidufexor Drugs 0.000 claims description 2
- JYTIXGYXBIBOMN-UHFFFAOYSA-N nidufexor Chemical compound Cn1nc(C(=O)N(Cc2ccccc2)Cc2ccc(cc2)C(O)=O)c2COc3ccc(Cl)cc3-c12 JYTIXGYXBIBOMN-UHFFFAOYSA-N 0.000 claims description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001597 nifedipine Drugs 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 2
- 229960001243 orlistat Drugs 0.000 claims description 2
- 229960003243 phenformin Drugs 0.000 claims description 2
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims description 2
- 229960005095 pioglitazone Drugs 0.000 claims description 2
- 229960002827 pioglitazone hydrochloride Drugs 0.000 claims description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 2
- 229960003611 pramlintide Drugs 0.000 claims description 2
- 229960002965 pravastatin Drugs 0.000 claims description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims description 2
- 229960004622 raloxifene Drugs 0.000 claims description 2
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 2
- 229960000371 rofecoxib Drugs 0.000 claims description 2
- 229960004586 rosiglitazone Drugs 0.000 claims description 2
- SUFUKZSWUHZXAV-BTJKTKAUSA-N rosiglitazone maleate Chemical compound [H+].[H+].[O-]C(=O)\C=C/C([O-])=O.C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O SUFUKZSWUHZXAV-BTJKTKAUSA-N 0.000 claims description 2
- 229960003271 rosiglitazone maleate Drugs 0.000 claims description 2
- 229960004937 saxagliptin Drugs 0.000 claims description 2
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 claims description 2
- 108010033693 saxagliptin Proteins 0.000 claims description 2
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 2
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 claims description 2
- 229960004425 sibutramine Drugs 0.000 claims description 2
- 229960002855 simvastatin Drugs 0.000 claims description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 2
- 229960004115 sitagliptin phosphate Drugs 0.000 claims description 2
- 208000019116 sleep disease Diseases 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 229960002935 telaprevir Drugs 0.000 claims description 2
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 claims description 2
- 108010017101 telaprevir Proteins 0.000 claims description 2
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 claims description 2
- 229960002722 terbinafine Drugs 0.000 claims description 2
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 claims description 2
- 230000003582 thrombocytopenic effect Effects 0.000 claims description 2
- 230000001732 thrombotic effect Effects 0.000 claims description 2
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 2
- 229960004699 valsartan Drugs 0.000 claims description 2
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 2
- 229960001254 vildagliptin Drugs 0.000 claims description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 2
- 235000019165 vitamin E Nutrition 0.000 claims description 2
- 229940046009 vitamin E Drugs 0.000 claims description 2
- 239000011709 vitamin E Substances 0.000 claims description 2
- 229960001729 voglibose Drugs 0.000 claims description 2
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 2
- 229960004740 voriconazole Drugs 0.000 claims description 2
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 claims description 2
- 102100028628 Bombesin receptor subtype-3 Human genes 0.000 claims 6
- 101000695054 Homo sapiens Bombesin receptor subtype-3 Proteins 0.000 claims 4
- 102100040918 Pro-glucagon Human genes 0.000 claims 4
- 102000003797 Neuropeptides Human genes 0.000 claims 3
- 108090000189 Neuropeptides Proteins 0.000 claims 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- 102100033367 Appetite-regulating hormone Human genes 0.000 claims 2
- 102000002148 Diacylglycerol O-acyltransferase Human genes 0.000 claims 2
- 108010001348 Diacylglycerol O-acyltransferase Proteins 0.000 claims 2
- 229940123037 Glucocorticoid antagonist Drugs 0.000 claims 2
- 229940086609 Lipase inhibitor Drugs 0.000 claims 2
- HBNPJJILLOYFJU-VMPREFPWSA-N Mibefradil Chemical compound C1CC2=CC(F)=CC=C2[C@H](C(C)C)[C@@]1(OC(=O)COC)CCN(C)CCCC1=NC2=CC=CC=C2N1 HBNPJJILLOYFJU-VMPREFPWSA-N 0.000 claims 2
- 102000008219 Uncoupling Protein 2 Human genes 0.000 claims 2
- 108010021111 Uncoupling Protein 2 Proteins 0.000 claims 2
- 102000008200 Uncoupling Protein 3 Human genes 0.000 claims 2
- 108010021098 Uncoupling Protein 3 Proteins 0.000 claims 2
- NEDPPCHNEOMTJV-UHFFFAOYSA-N aldesulfone Chemical compound C1=CC(NCS(=O)O)=CC=C1S(=O)(=O)C1=CC=C(NCS(O)=O)C=C1 NEDPPCHNEOMTJV-UHFFFAOYSA-N 0.000 claims 2
- 229950006704 aldesulfone Drugs 0.000 claims 2
- 108010063504 bombesin receptor subtype 3 Proteins 0.000 claims 2
- 239000005516 coenzyme A Substances 0.000 claims 2
- 229940093530 coenzyme a Drugs 0.000 claims 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims 2
- 229960004961 mechlorethamine Drugs 0.000 claims 2
- 229960004438 mibefradil Drugs 0.000 claims 2
- WIQRCHMSJFFONW-UHFFFAOYSA-N norfluoxetine Chemical compound C=1C=CC=CC=1C(CCN)OC1=CC=C(C(F)(F)F)C=C1 WIQRCHMSJFFONW-UHFFFAOYSA-N 0.000 claims 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims 2
- IETKPTYAGKZLKY-UHFFFAOYSA-N 5-[[4-[(3-methyl-4-oxoquinazolin-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound N=1C2=CC=CC=C2C(=O)N(C)C=1COC(C=C1)=CC=C1CC1SC(=O)NC1=O IETKPTYAGKZLKY-UHFFFAOYSA-N 0.000 claims 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims 1
- 208000003174 Brain Neoplasms Diseases 0.000 claims 1
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims 1
- 229940123169 Caspase inhibitor Drugs 0.000 claims 1
- 206010009208 Cirrhosis alcoholic Diseases 0.000 claims 1
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 claims 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 claims 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 claims 1
- 241000209219 Hordeum Species 0.000 claims 1
- 235000007340 Hordeum vulgare Nutrition 0.000 claims 1
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 claims 1
- 206010025323 Lymphomas Diseases 0.000 claims 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 claims 1
- 108010006519 Molecular Chaperones Proteins 0.000 claims 1
- 102000007072 Nerve Growth Factors Human genes 0.000 claims 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 claims 1
- 229940123185 Squalene epoxidase inhibitor Drugs 0.000 claims 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 claims 1
- 208000010002 alcoholic liver cirrhosis Diseases 0.000 claims 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 claims 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 claims 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims 1
- 230000003276 anti-hypertensive effect Effects 0.000 claims 1
- 229940125708 antidiabetic agent Drugs 0.000 claims 1
- 229950010663 balaglitazone Drugs 0.000 claims 1
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 claims 1
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 claims 1
- 229950009226 ciglitazone Drugs 0.000 claims 1
- 230000001886 ciliary effect Effects 0.000 claims 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims 1
- 208000016097 disease of metabolism Diseases 0.000 claims 1
- 239000000221 dopamine uptake inhibitor Substances 0.000 claims 1
- 230000003176 fibrotic effect Effects 0.000 claims 1
- 108010077689 gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide Proteins 0.000 claims 1
- 229960002397 linagliptin Drugs 0.000 claims 1
- 229960001110 miglitol Drugs 0.000 claims 1
- 229930189775 mogroside Natural products 0.000 claims 1
- 239000003900 neurotrophic factor Substances 0.000 claims 1
- 229960005489 paracetamol Drugs 0.000 claims 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims 1
- 239000002464 receptor antagonist Substances 0.000 claims 1
- 239000002469 receptor inverse agonist Substances 0.000 claims 1
- 229940075993 receptor modulator Drugs 0.000 claims 1
- 208000020685 sleep-wake disease Diseases 0.000 claims 1
- 201000007455 central nervous system cancer Diseases 0.000 abstract 1
- 108091051828 miR-122 stem-loop Proteins 0.000 description 124
- 108091007780 MiR-122 Proteins 0.000 description 123
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 100
- 229940125904 compound 1 Drugs 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 80
- 230000000694 effects Effects 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 241000699670 Mus sp. Species 0.000 description 53
- 239000007787 solid Substances 0.000 description 49
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 238000003786 synthesis reaction Methods 0.000 description 35
- 229940079593 drug Drugs 0.000 description 34
- 239000002245 particle Substances 0.000 description 27
- 229910001868 water Inorganic materials 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 26
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 108090000623 proteins and genes Proteins 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 239000007858 starting material Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 235000009200 high fat diet Nutrition 0.000 description 21
- 230000001965 increasing effect Effects 0.000 description 21
- 239000011780 sodium chloride Substances 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- 239000002679 microRNA Substances 0.000 description 20
- 210000001519 tissue Anatomy 0.000 description 19
- 230000009467 reduction Effects 0.000 description 18
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 230000009286 beneficial effect Effects 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 108060001084 Luciferase Proteins 0.000 description 14
- 239000005089 Luciferase Substances 0.000 description 14
- 125000003277 amino group Chemical group 0.000 description 14
- 230000002440 hepatic effect Effects 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 238000002347 injection Methods 0.000 description 14
- 108091070501 miRNA Proteins 0.000 description 14
- 210000003205 muscle Anatomy 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 230000001105 regulatory effect Effects 0.000 description 14
- 239000003381 stabilizer Substances 0.000 description 14
- 238000011529 RT qPCR Methods 0.000 description 13
- 230000004913 activation Effects 0.000 description 13
- 230000037396 body weight Effects 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 108700011259 MicroRNAs Proteins 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 230000028327 secretion Effects 0.000 description 12
- 238000010186 staining Methods 0.000 description 12
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 11
- 238000011740 C57BL/6 mouse Methods 0.000 description 11
- 230000009102 absorption Effects 0.000 description 11
- 238000010521 absorption reaction Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000002872 contrast media Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 230000004761 fibrosis Effects 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- 230000007246 mechanism Effects 0.000 description 11
- 229920000642 polymer Polymers 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 230000002194 synthesizing effect Effects 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 206010016654 Fibrosis Diseases 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- 239000002502 liposome Substances 0.000 description 10
- 230000001404 mediated effect Effects 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 239000013612 plasmid Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 210000000068 Th17 cell Anatomy 0.000 description 9
- 210000000593 adipose tissue white Anatomy 0.000 description 9
- 230000002776 aggregation Effects 0.000 description 9
- 230000004888 barrier function Effects 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 230000008499 blood brain barrier function Effects 0.000 description 9
- 210000001218 blood-brain barrier Anatomy 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 208000006454 hepatitis Diseases 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 230000000512 lipotoxic effect Effects 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 108020004999 messenger RNA Proteins 0.000 description 9
- 230000003442 weekly effect Effects 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 108010052090 Renilla Luciferases Proteins 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 8
- 208000019425 cirrhosis of liver Diseases 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 150000002367 halogens Chemical class 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000002503 metabolic effect Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 description 7
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 description 7
- 241000282412 Homo Species 0.000 description 7
- 241000725303 Human immunodeficiency virus Species 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 230000000840 anti-viral effect Effects 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 210000002540 macrophage Anatomy 0.000 description 7
- 230000036470 plasma concentration Effects 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 238000011002 quantification Methods 0.000 description 7
- 230000032258 transport Effects 0.000 description 7
- 230000004580 weight loss Effects 0.000 description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 239000000853 adhesive Substances 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
- 210000003494 hepatocyte Anatomy 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 230000001976 improved effect Effects 0.000 description 6
- 230000006372 lipid accumulation Effects 0.000 description 6
- 208000018191 liver inflammation Diseases 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 230000035515 penetration Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 231100000240 steatosis hepatitis Toxicity 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 230000005526 G1 to G0 transition Effects 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 108700009124 Transcription Initiation Site Proteins 0.000 description 5
- 230000001070 adhesive effect Effects 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 230000037213 diet Effects 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 230000012202 endocytosis Effects 0.000 description 5
- 235000021588 free fatty acids Nutrition 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 108020001756 ligand binding domains Proteins 0.000 description 5
- 230000037356 lipid metabolism Effects 0.000 description 5
- 210000004324 lymphatic system Anatomy 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 4
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 208000004930 Fatty Liver Diseases 0.000 description 4
- 108090000331 Firefly luciferases Proteins 0.000 description 4
- 206010019708 Hepatic steatosis Diseases 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 238000002123 RNA extraction Methods 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 4
- 125000001769 aryl amino group Chemical group 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 208000027697 autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency Diseases 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000010805 cDNA synthesis kit Methods 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 150000002191 fatty alcohols Chemical class 0.000 description 4
- 239000012894 fetal calf serum Substances 0.000 description 4
- 239000010408 film Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- CNJJSTPBUHAEFH-UHFFFAOYSA-N methyl 4-fluoro-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(F)C([N+]([O-])=O)=C1 CNJJSTPBUHAEFH-UHFFFAOYSA-N 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 210000002027 skeletal muscle Anatomy 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 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 4
- 239000000725 suspension Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 3
- 229940035437 1,3-propanediol Drugs 0.000 description 3
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- ABGXADJDTPFFSZ-UHFFFAOYSA-N 4-benzylpiperidine Chemical compound C=1C=CC=CC=1CC1CCNCC1 ABGXADJDTPFFSZ-UHFFFAOYSA-N 0.000 description 3
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108091032955 Bacterial small RNA Proteins 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- WNAZYCXCUUJPGQ-UHFFFAOYSA-N COC(=O)C1=C(C=CC=C1)NC1=C(C=C(C(=O)OC)C=C1)[N+](=O)[O-] Chemical compound COC(=O)C1=C(C=CC=C1)NC1=C(C=C(C(=O)OC)C=C1)[N+](=O)[O-] WNAZYCXCUUJPGQ-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 102000013691 Interleukin-17 Human genes 0.000 description 3
- 108050003558 Interleukin-17 Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 3
- 206010057249 Phagocytosis Diseases 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000036436 anti-hiv Effects 0.000 description 3
- 229920001400 block copolymer Polymers 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 229940125900 compound 59 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000412 dendrimer Substances 0.000 description 3
- 229920000736 dendritic polymer Polymers 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000002059 diagnostic imaging Methods 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 208000010706 fatty liver disease Diseases 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- GBHMIPUQOZMFKW-UHFFFAOYSA-N methyl 8-bromo-6-oxo-5,11-dihydrobenzo[b][1,4]benzodiazepine-3-carboxylate Chemical compound N1C2=C(NC(=O)C3=CC(=CC=C13)Br)C=C(C(=O)OC)C=C2 GBHMIPUQOZMFKW-UHFFFAOYSA-N 0.000 description 3
- 108091027698 miR-18-1 stem-loop Proteins 0.000 description 3
- 108091090961 miR-18-2 stem-loop Proteins 0.000 description 3
- 108091090568 miR-39 stem-loop Proteins 0.000 description 3
- 108091056739 miR-39-1 stem-loop Proteins 0.000 description 3
- 108091039160 miR-39-2 stem-loop Proteins 0.000 description 3
- 230000004682 mucosal barrier function Effects 0.000 description 3
- 229960002009 naproxen Drugs 0.000 description 3
- CMWTZPSULFXXJA-VIFPVBQESA-M naproxen(1-) Chemical compound C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-M 0.000 description 3
- 108020004017 nuclear receptors Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000008782 phagocytosis Effects 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 229920001987 poloxamine Polymers 0.000 description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 231100000272 reduced body weight Toxicity 0.000 description 3
- 108090000064 retinoic acid receptors Proteins 0.000 description 3
- 102000003702 retinoic acid receptors Human genes 0.000 description 3
- KFQYTPMOWPVWEJ-INIZCTEOSA-N rotigotine Chemical compound CCCN([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000002047 solid lipid nanoparticle Substances 0.000 description 3
- 230000007863 steatosis Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 229920001664 tyloxapol Polymers 0.000 description 3
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 3
- 229960004224 tyloxapol Drugs 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 2
- HLHYXXBCQOUTGK-FHCQLJOMSA-N (7R,14S)-dihydroxy-(4Z,8E,10E,12Z,16Z,19Z)-docosahexaenoic acid Chemical compound CC\C=C/C\C=C/C[C@H](O)\C=C/C=C/C=C/[C@H](O)C\C=C/CCC(O)=O HLHYXXBCQOUTGK-FHCQLJOMSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- RATZLMXRALDSJW-UHFFFAOYSA-N 2-(2-ethyl-3H-benzofuran-2-yl)-4,5-dihydro-1H-imidazole Chemical compound C1C2=CC=CC=C2OC1(CC)C1=NCCN1 RATZLMXRALDSJW-UHFFFAOYSA-N 0.000 description 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- RRRVZQRJBFXHFP-UHFFFAOYSA-N 3-(4-benzylpiperazine-1-carbonyl)-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound C=1C=C2NC3=CC=CC=C3C(=O)NC2=CC=1C(=O)N(CC1)CCN1CC1=CC=CC=C1 RRRVZQRJBFXHFP-UHFFFAOYSA-N 0.000 description 2
- FJAJUBMJYQZUCQ-UHFFFAOYSA-N 3-(4-benzylpiperidine-1-carbonyl)-11-methyl-5H-benzo[b][1,4]benzodiazepin-6-one Chemical compound C1(CCN(CC1)C(=O)C1=CC=2NC(=O)C3=CC=CC=C3N(C)C=2C=C1)CC1=CC=CC=C1 FJAJUBMJYQZUCQ-UHFFFAOYSA-N 0.000 description 2
- OQVJIYMIASPEGG-UHFFFAOYSA-N 3-(4-benzylpiperidine-1-carbonyl)-5,11-dimethylbenzo[b][1,4]benzodiazepin-6-one Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C1=CC=2N(C(=O)C3=CC=CC=C3N(C)C=2C=C1)C OQVJIYMIASPEGG-UHFFFAOYSA-N 0.000 description 2
- DSLMVTHVEIBLDL-UHFFFAOYSA-N 3-(4-benzylpiperidine-1-carbonyl)-5-methyl-11H-benzo[b][1,4]benzodiazepin-6-one Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(N(C(C3=C(N2)C=CC=C3)=O)C)C=1 DSLMVTHVEIBLDL-UHFFFAOYSA-N 0.000 description 2
- ORMLMZYYHPPFRY-UHFFFAOYSA-N 3-(4-benzylpiperidine-1-carbonyl)-8-bromo-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound C(C1CCN(CC1)C(=O)C1=CC2=C(NC3=C(C=C(Br)C=C3)C(=O)N2)C=C1)C1=CC=CC=C1 ORMLMZYYHPPFRY-UHFFFAOYSA-N 0.000 description 2
- WXZWYZGSADVUCO-UHFFFAOYSA-N 3-(4-benzylpiperidine-1-carbonyl)-8-ethenyl-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound C1(CCN(CC1)C(=O)C1=CC=C2NC3=C(C=C(C=C)C=C3)C(=O)NC2=C1)CC1=CC=CC=C1 WXZWYZGSADVUCO-UHFFFAOYSA-N 0.000 description 2
- FNMBMFRXLUOYBF-UHFFFAOYSA-N 3-(4-benzylpiperidine-1-carbonyl)-8-ethynyl-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C#C)=O)C=1 FNMBMFRXLUOYBF-UHFFFAOYSA-N 0.000 description 2
- QMSICWCZDWFQDV-UHFFFAOYSA-N 3-(4-phenylpiperazine-1-carbonyl)-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound O=C(C(C=C1)=CC(N2)=C1NC(C=CC=C1)=C1C2=O)N(CC1)CCN1C1=CC=CC=C1 QMSICWCZDWFQDV-UHFFFAOYSA-N 0.000 description 2
- IJOGOPZHYKUWAE-UHFFFAOYSA-N 3-(morpholine-4-carbonyl)-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound C=1C=C2NC3=CC=CC=C3C(=O)NC2=CC=1C(=O)N1CCOCC1 IJOGOPZHYKUWAE-UHFFFAOYSA-N 0.000 description 2
- QMDQOSQCWIWQGD-UHFFFAOYSA-N 3-(piperidine-1-carbonyl)-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound C=1C=C2NC3=CC=CC=C3C(=O)NC2=CC=1C(=O)N1CCCCC1 QMDQOSQCWIWQGD-UHFFFAOYSA-N 0.000 description 2
- DMABATSJIJZLCM-UHFFFAOYSA-N 3-[4-(2-phenylethyl)piperidine-1-carbonyl]-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound N1C2=C(NC(=O)C3=CC=CC=C13)C=C(C(=O)N1CCC(CC1)CCC1=CC=CC=C1)C=C2 DMABATSJIJZLCM-UHFFFAOYSA-N 0.000 description 2
- CLOAVFRIRNNWIN-UHFFFAOYSA-N 3-[4-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-5,11-dihydrobenzo[b][1,4]benzodiazepin-6-one Chemical compound O=C(C(C=C1)=CC(N2)=C1NC(C=CC=C1)=C1C2=O)N1CCC(CC(C=C2)=CC=C2F)CC1 CLOAVFRIRNNWIN-UHFFFAOYSA-N 0.000 description 2
- CXSJJPTZIODQCE-UHFFFAOYSA-N 3-amino-4-(2-carboxyanilino)benzoic acid Chemical compound NC=1C=C(C(=O)O)C=CC=1NC1=C(C=CC=C1)C(=O)O CXSJJPTZIODQCE-UHFFFAOYSA-N 0.000 description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 2
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 2
- DJOWOQXLUCTXPY-UHFFFAOYSA-N 6-oxo-5,11-dihydrobenzo[b][1,4]benzodiazepine-3-carboxylic acid Chemical compound O=C1NC2=CC(C(=O)O)=CC=C2NC2=CC=CC=C21 DJOWOQXLUCTXPY-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- GUFMKIUPADFTKQ-UHFFFAOYSA-N 8-bromo-6-oxo-5,11-dihydrobenzo[b][1,4]benzodiazepine-3-carboxylic acid Chemical compound N1C2=C(NC(=O)C3=CC(=CC=C13)Br)C=C(C(=O)O)C=C2 GUFMKIUPADFTKQ-UHFFFAOYSA-N 0.000 description 2
- DPTZOOXIEWHODB-UHFFFAOYSA-N 9alpha-hydroxy-6beta-[(2E,4E,6E)-octa-2,4,6-trienoyloxy]-5alpha-drim-7-en-11,12-olide Natural products CC12CCCC(C)(C)C1C(OC(=O)C=CC=CC=CC)C=C1C2(O)C(=O)OC1 DPTZOOXIEWHODB-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- 101150037140 Aldoa gene Proteins 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 206010064539 Autoimmune myocarditis Diseases 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- FTKSRLOXBFDFFP-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC=C3)=O)C=1 Chemical compound C(C1=CC=CC=C1)(=O)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC=C3)=O)C=1 FTKSRLOXBFDFFP-UHFFFAOYSA-N 0.000 description 2
- AXRIBLVTKOELKH-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(N(C(C3=C(N2)C=CC=C3)=O)CCCC)C=1 Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(N(C(C3=C(N2)C=CC=C3)=O)CCCC)C=1 AXRIBLVTKOELKH-UHFFFAOYSA-N 0.000 description 2
- CMYUALVRKIXMQB-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C2=CC=C(C(=O)OC)C=C2)=O)C=1 Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C2=CC=C(C(=O)OC)C=C2)=O)C=1 CMYUALVRKIXMQB-UHFFFAOYSA-N 0.000 description 2
- GQQGSWYGYHEQQE-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C2=CC=C(C=C2)OC(F)(F)F)=O)C=1 Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C2=CC=C(C=C2)OC(F)(F)F)=O)C=1 GQQGSWYGYHEQQE-UHFFFAOYSA-N 0.000 description 2
- USVHFSKXBGTNNO-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C2=CC=C(C=C2)S(=O)(=O)C)=O)C=1 Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C2=CC=C(C=C2)S(=O)(=O)C)=O)C=1 USVHFSKXBGTNNO-UHFFFAOYSA-N 0.000 description 2
- LQCYWCCKUYGZHV-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C=2C=NC=CC=2)=O)C=1 Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C=2C=NC=CC=2)=O)C=1 LQCYWCCKUYGZHV-UHFFFAOYSA-N 0.000 description 2
- ZIBIPEMVFVZQCW-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C=2C=NNC=2)=O)C=1 Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC(=C3)C=2C=NNC=2)=O)C=1 ZIBIPEMVFVZQCW-UHFFFAOYSA-N 0.000 description 2
- ZEGGVUVIXLILGR-UHFFFAOYSA-N C(C1=CC=CC=C1)N1C2=C(NC3=C(C1=O)C=CC=C3)C=CC(=C2)C(=O)N1CCC(CC1)CC1=CC=CC=C1 Chemical compound C(C1=CC=CC=C1)N1C2=C(NC3=C(C1=O)C=CC=C3)C=CC(=C2)C(=O)N1CCC(CC1)CC1=CC=CC=C1 ZEGGVUVIXLILGR-UHFFFAOYSA-N 0.000 description 2
- NAIRBDSQPTUQDJ-UHFFFAOYSA-N C1(=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC=C3)=O)C=1 Chemical compound C1(=CC=CC=C1)C1CCN(CC1)C(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC=C3)=O)C=1 NAIRBDSQPTUQDJ-UHFFFAOYSA-N 0.000 description 2
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 2
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 2
- YFXCFXSVNFMUTJ-UHFFFAOYSA-N COC(=O)c1ccc(Nc2ccccc2C(=O)OC)c(N)c1 Chemical compound COC(=O)c1ccc(Nc2ccccc2C(=O)OC)c(N)c1 YFXCFXSVNFMUTJ-UHFFFAOYSA-N 0.000 description 2
- 108091070482 Caenorhabditis elegans miR-39 stem-loop Proteins 0.000 description 2
- BAVONGHXFVOKBV-UHFFFAOYSA-N Carveol Chemical compound CC(=C)C1CC=C(C)C(O)C1 BAVONGHXFVOKBV-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 101150042222 DGAT1 gene Proteins 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- MGJCZCLBCSTIHG-UHFFFAOYSA-N FC1=C(CC2CCN(CC2)C(=O)C=2C=CC3=C(NC(C4=C(N3)C=CC=C4)=O)C=2)C=CC=C1 Chemical compound FC1=C(CC2CCN(CC2)C(=O)C=2C=CC3=C(NC(C4=C(N3)C=CC=C4)=O)C=2)C=CC=C1 MGJCZCLBCSTIHG-UHFFFAOYSA-N 0.000 description 2
- GSARYKUZTGRFAM-UHFFFAOYSA-N FC=1C=C(CC2CCN(CC2)C(=O)C=2C=CC3=C(NC(C4=C(N3)C=CC=C4)=O)C=2)C=CC=1 Chemical compound FC=1C=C(CC2CCN(CC2)C(=O)C=2C=CC3=C(NC(C4=C(N3)C=CC=C4)=O)C=2)C=CC=1 GSARYKUZTGRFAM-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 2
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 2
- 102400000322 Glucagon-like peptide 1 Human genes 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
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 2
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 2
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 2
- 241000254158 Lampyridae Species 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 241001421711 Mithras Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- RZKJVALKZPQEAX-UHFFFAOYSA-N N-nonyl-6-oxo-5,11-dihydrobenzo[b][1,4]benzodiazepine-3-carboxamide Chemical compound CCCCCCCCCNC(C(C=C1)=CC(N2)=C1NC(C=CC=C1)=C1C2=O)=O RZKJVALKZPQEAX-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- NPPATLYTBDANLM-UHFFFAOYSA-N N1(C=NC=C1)CCCNC(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC=C3)=O)C=1 Chemical compound N1(C=NC=C1)CCCNC(=O)C=1C=CC2=C(NC(C3=C(N2)C=CC=C3)=O)C=1 NPPATLYTBDANLM-UHFFFAOYSA-N 0.000 description 2
- 238000013231 NASH rodent model Methods 0.000 description 2
- XEAQQDHCRHVRHF-UHFFFAOYSA-N O1C(=CC2=C1C=CC=C2)C1=CC2=C(NC3=C(NC2=O)C=C(C=C3)C(=O)N2CCC(CC2)CC2=CC=CC=C2)C=C1 Chemical compound O1C(=CC2=C1C=CC=C2)C1=CC2=C(NC3=C(NC2=O)C=C(C=C3)C(=O)N2CCC(CC2)CC2=CC=CC=C2)C=C1 XEAQQDHCRHVRHF-UHFFFAOYSA-N 0.000 description 2
- 238000009004 PCR Kit Methods 0.000 description 2
- 241000282579 Pan Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- FOLJTMYCYXSPFQ-CJKAUBRRSA-N [(2r,3s,4s,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-(octadecanoyloxymethyl)oxolan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl octadecanoate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)CCCCCCCCCCCCCCCCC)O[C@@H]1O[C@@]1(COC(=O)CCCCCCCCCCCCCCCCC)[C@@H](O)[C@H](O)[C@@H](CO)O1 FOLJTMYCYXSPFQ-CJKAUBRRSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 230000000923 atherogenic effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000012925 biological evaluation Methods 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 230000003081 coactivator Effects 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000011437 continuous method Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229950001765 efaroxan Drugs 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 230000004153 glucose metabolism Effects 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 150000002634 lipophilic molecules Chemical class 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000001055 magnesium Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- AAPLXOZEWBRBKT-UHFFFAOYSA-N methyl 3-amino-4-(4-bromo-2-methoxycarbonylanilino)benzoate Chemical compound NC1=C(C=CC(=C1)C(=O)OC)NC1=C(C(=O)OC)C=C(C=C1)Br AAPLXOZEWBRBKT-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 108091032902 miR-93 stem-loop Proteins 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 102000027507 nuclear receptors type II Human genes 0.000 description 2
- 108091008686 nuclear receptors type II Proteins 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- SJGALSBBFTYSBA-UHFFFAOYSA-N oxaziridine Chemical compound C1NO1 SJGALSBBFTYSBA-UHFFFAOYSA-N 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 208000028169 periodontal disease Diseases 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229960003179 rotigotine Drugs 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229960004274 stearic acid Drugs 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000003871 sulfonates Chemical class 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 210000001578 tight junction Anatomy 0.000 description 2
- 230000031998 transcytosis Effects 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 description 2
- BAVONGHXFVOKBV-ZJUUUORDSA-N (-)-trans-carveol Natural products CC(=C)[C@@H]1CC=C(C)[C@@H](O)C1 BAVONGHXFVOKBV-ZJUUUORDSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- JVAZJLFFSJARQM-RMPHRYRLSA-N (2r,3r,4s,5s,6r)-2-hexoxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound CCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JVAZJLFFSJARQM-RMPHRYRLSA-N 0.000 description 1
- HEGSGKPQLMEBJL-RQICVUQASA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-6-octoxyoxane-3,4,5-triol Chemical compound CCCCCCCCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RQICVUQASA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- JDRSMPFHFNXQRB-IWQYDBTJSA-N (3r,4s,5s,6r)-2-decoxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound CCCCCCCCCCOC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JDRSMPFHFNXQRB-IWQYDBTJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- CALDMMCNNFPJSI-CRCLSJGQSA-N (3r,5s)-5-(hydroxymethyl)pyrrolidin-3-ol Chemical compound OC[C@@H]1C[C@@H](O)CN1 CALDMMCNNFPJSI-CRCLSJGQSA-N 0.000 description 1
- SCVHJVCATBPIHN-SJCJKPOMSA-N (3s)-3-[[(2s)-2-[[2-(2-tert-butylanilino)-2-oxoacetyl]amino]propanoyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid Chemical compound N([C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)COC=1C(=C(F)C=C(F)C=1F)F)C(=O)C(=O)NC1=CC=CC=C1C(C)(C)C SCVHJVCATBPIHN-SJCJKPOMSA-N 0.000 description 1
- GNRHNKBJNUVWFZ-UHFFFAOYSA-N (4-carbamoylphenyl)boronic acid Chemical group NC(=O)C1=CC=C(B(O)O)C=C1 GNRHNKBJNUVWFZ-UHFFFAOYSA-N 0.000 description 1
- PQCXFUXRTRESBD-UHFFFAOYSA-N (4-methoxycarbonylphenyl)boronic acid Chemical group COC(=O)C1=CC=C(B(O)O)C=C1 PQCXFUXRTRESBD-UHFFFAOYSA-N 0.000 description 1
- VDUKDQTYMWUSAC-UHFFFAOYSA-N (4-methylsulfonylphenyl)boronic acid Chemical group CS(=O)(=O)C1=CC=C(B(O)O)C=C1 VDUKDQTYMWUSAC-UHFFFAOYSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- CCEFMUBVSUDRLG-KXUCPTDWSA-N (4R)-limonene 1,2-epoxide Natural products C1[C@H](C(=C)C)CC[C@@]2(C)O[C@H]21 CCEFMUBVSUDRLG-KXUCPTDWSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- WUOACPNHFRMFPN-SECBINFHSA-N (S)-(-)-alpha-terpineol Chemical compound CC1=CC[C@@H](C(C)(C)O)CC1 WUOACPNHFRMFPN-SECBINFHSA-N 0.000 description 1
- RYSXWUYLAWPLES-MTOQALJVSA-N (Z)-4-hydroxypent-3-en-2-one titanium Chemical compound [Ti].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O RYSXWUYLAWPLES-MTOQALJVSA-N 0.000 description 1
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- ICSWLKDKQBNKAY-UHFFFAOYSA-N 1,1,3,3,5,5-hexamethyl-1,3,5-trisilinane Chemical compound C[Si]1(C)C[Si](C)(C)C[Si](C)(C)C1 ICSWLKDKQBNKAY-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical class C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- OMIVCRYZSXDGAB-UHFFFAOYSA-N 1,4-butanediyl Chemical group [CH2]CC[CH2] OMIVCRYZSXDGAB-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 102100030408 1-acyl-sn-glycerol-3-phosphate acyltransferase alpha Human genes 0.000 description 1
- PKRRNTJIHGOMRC-UHFFFAOYSA-N 1-benzofuran-2-ylboronic acid Chemical group C1=CC=C2OC(B(O)O)=CC2=C1 PKRRNTJIHGOMRC-UHFFFAOYSA-N 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- BPIUIOXAFBGMNB-UHFFFAOYSA-N 1-hexoxyhexane Chemical compound CCCCCCOCCCCCC BPIUIOXAFBGMNB-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GRWFGVWFFZKLTI-IUCAKERBSA-N 1S,5S-(-)-alpha-Pinene Natural products CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 description 1
- GEWRKGDRYZIFNP-UHFFFAOYSA-N 1h-1,3,5-triazine-2,4-dione Chemical compound OC1=NC=NC(O)=N1 GEWRKGDRYZIFNP-UHFFFAOYSA-N 0.000 description 1
- KEZNMOUMHOZFRA-UHFFFAOYSA-N 1h-pyrazol-4-ylboronic acid Chemical group OB(O)C=1C=NNC=1 KEZNMOUMHOZFRA-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical group N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- NQFUSWIGRKFAHK-UHFFFAOYSA-N 2,3-epoxypinane Chemical compound CC12OC1CC1C(C)(C)C2C1 NQFUSWIGRKFAHK-UHFFFAOYSA-N 0.000 description 1
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical group C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- RLFZYIUUQBHRNV-UHFFFAOYSA-N 2,5-dihydrooxadiazole Chemical group C1ONN=C1 RLFZYIUUQBHRNV-UHFFFAOYSA-N 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- VVCMGAUPZIKYTH-VGHSCWAPSA-N 2-acetyloxybenzoic acid;[(2s,3r)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 VVCMGAUPZIKYTH-VGHSCWAPSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- OEZPDHRXGCLGKB-UHFFFAOYSA-N 2-chloropropanamide Chemical compound CC(Cl)C(N)=O OEZPDHRXGCLGKB-UHFFFAOYSA-N 0.000 description 1
- WDQMWEYDKDCEHT-UHFFFAOYSA-N 2-ethylhexyl 2-methylprop-2-enoate Chemical compound CCCCC(CC)COC(=O)C(C)=C WDQMWEYDKDCEHT-UHFFFAOYSA-N 0.000 description 1
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 description 1
- KIHAGWUUUHJRMS-JOCHJYFZSA-N 2-octadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@H](CO)COP(O)(=O)OCCN KIHAGWUUUHJRMS-JOCHJYFZSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 1
- YPEONYJCVGSTMP-UHFFFAOYSA-N 2-phenyl-1-piperidin-4-ylethanone Chemical compound C1CNCCC1C(=O)CC1=CC=CC=C1 YPEONYJCVGSTMP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- LGCYVLDNGBSOOW-UHFFFAOYSA-N 2H-benzotriazol-4-ol 1-hydroxybenzotriazole Chemical compound OC1=CC=CC2=C1N=NN2.C1=CC=C2N(O)N=NC2=C1 LGCYVLDNGBSOOW-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical group N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- XBIUWALDKXACEA-UHFFFAOYSA-N 3-[bis(2,4-dioxopentan-3-yl)alumanyl]pentane-2,4-dione Chemical compound CC(=O)C(C(C)=O)[Al](C(C(C)=O)C(C)=O)C(C(C)=O)C(C)=O XBIUWALDKXACEA-UHFFFAOYSA-N 0.000 description 1
- KDHWOCLBMVSZPG-UHFFFAOYSA-N 3-imidazol-1-ylpropan-1-amine Chemical compound NCCCN1C=CN=C1 KDHWOCLBMVSZPG-UHFFFAOYSA-N 0.000 description 1
- WFTPSTRUUZKFRH-UHFFFAOYSA-N 4-(2-phenylethyl)piperidine Chemical compound C1CNCCC1CCC1=CC=CC=C1 WFTPSTRUUZKFRH-UHFFFAOYSA-N 0.000 description 1
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 1
- HPTZGYXMDTTYBG-UHFFFAOYSA-N 4-[(2-fluorophenyl)methyl]piperidine Chemical compound FC1=CC=CC=C1CC1CCNCC1 HPTZGYXMDTTYBG-UHFFFAOYSA-N 0.000 description 1
- XZRQMBCQGGXDKQ-UHFFFAOYSA-N 4-[(3-fluorophenyl)methyl]piperidine;hydrochloride Chemical compound Cl.FC1=CC=CC(CC2CCNCC2)=C1 XZRQMBCQGGXDKQ-UHFFFAOYSA-N 0.000 description 1
- MINMDCMSHDBHKG-UHFFFAOYSA-N 4-[4-[[6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-1-benzofuran-4-yl]oxymethyl]-5-methyl-1,3-thiazol-2-yl]morpholine Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(=C(S1)C)N=C1N1CCOCC1 MINMDCMSHDBHKG-UHFFFAOYSA-N 0.000 description 1
- BOJWTAQWPVBIPG-UHFFFAOYSA-N 4-fluoro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C([N+]([O-])=O)=C1 BOJWTAQWPVBIPG-UHFFFAOYSA-N 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- NPYPQKXJJZZSAX-UHFFFAOYSA-N 5-benzylpyrimidine Chemical compound C=1N=CN=CC=1CC1=CC=CC=C1 NPYPQKXJJZZSAX-UHFFFAOYSA-N 0.000 description 1
- HXXVIKZQIFTJOQ-UHFFFAOYSA-N 5-ethenylpyrimidine Chemical compound C=CC1=CN=CN=C1 HXXVIKZQIFTJOQ-UHFFFAOYSA-N 0.000 description 1
- PVRBGBGMDLPYKG-UHFFFAOYSA-N 6-benzyl-7h-purine Chemical compound N=1C=NC=2N=CNC=2C=1CC1=CC=CC=C1 PVRBGBGMDLPYKG-UHFFFAOYSA-N 0.000 description 1
- DBCMWACNZJYUHS-UHFFFAOYSA-N 6-ethenyl-7h-purine Chemical compound C=CC1=NC=NC2=C1NC=N2 DBCMWACNZJYUHS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 229940127438 Amylin Agonists Drugs 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 1
- 102100025074 C-C chemokine receptor-like 2 Human genes 0.000 description 1
- 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 description 1
- RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000014882 Carotid artery disease Diseases 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- BHYOQNUELFTYRT-UHFFFAOYSA-N Cholesterol sulfate Natural products C1C=C2CC(OS(O)(=O)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 BHYOQNUELFTYRT-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 1
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102000000989 Complement System Proteins Human genes 0.000 description 1
- 108010069112 Complement System Proteins Proteins 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 101000785223 Crocosmia x crocosmiiflora Myricetin 3-O-glucosyl 1,2-rhamnoside 6'-O-caffeoyltransferase AT1 Proteins 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 241000101840 Ctenolophon parvifolius Species 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 description 1
- KKUKTXOBAWVSHC-UHFFFAOYSA-N Dimethylphosphate Chemical class COP(O)(=O)OC KKUKTXOBAWVSHC-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000003718 Dual-Luciferase Reporter Assay System Methods 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 101150023900 G6PC1 gene Proteins 0.000 description 1
- 102400000442 Ghrelin-28 Human genes 0.000 description 1
- 102100036264 Glucose-6-phosphatase catalytic subunit 1 Human genes 0.000 description 1
- 101710099339 Glucose-6-phosphatase catalytic subunit 1 Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 238000013218 HFD mouse model Methods 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 101000583049 Homo sapiens 1-acyl-sn-glycerol-3-phosphate acyltransferase alpha Proteins 0.000 description 1
- 101000716068 Homo sapiens C-C chemokine receptor type 6 Proteins 0.000 description 1
- 101000927974 Homo sapiens Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101001122938 Homo sapiens Lysosomal protective protein Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 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
- CCEFMUBVSUDRLG-XNWIYYODSA-N Limonene-1,2-epoxide Chemical compound C1[C@H](C(=C)C)CCC2(C)OC21 CCEFMUBVSUDRLG-XNWIYYODSA-N 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 102100028524 Lysosomal protective protein Human genes 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 235000001412 Mediterranean diet Nutrition 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 108091028066 Mir-126 Proteins 0.000 description 1
- 102000015728 Mucins Human genes 0.000 description 1
- 108010063954 Mucins Proteins 0.000 description 1
- IRLWJILLXJGJTD-UHFFFAOYSA-N Muraglitazar Chemical compound C1=CC(OC)=CC=C1OC(=O)N(CC(O)=O)CC(C=C1)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 IRLWJILLXJGJTD-UHFFFAOYSA-N 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 101100348097 Mus musculus Ncor2 gene Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000609499 Palicourea Species 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 241000320380 Silybum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 241000519995 Stachys sylvatica Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 229920004482 WACKER® Polymers 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- HUOFUOCSQCYFPW-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]boronic acid Chemical group OB(O)C1=CC=C(OC(F)(F)F)C=C1 HUOFUOCSQCYFPW-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 208000002353 alcoholic hepatitis Diseases 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- OVKDFILSBMEKLT-UHFFFAOYSA-N alpha-Terpineol Natural products CC(=C)C1(O)CCC(C)=CC1 OVKDFILSBMEKLT-UHFFFAOYSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 description 1
- 229940088601 alpha-terpineol Drugs 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 210000001132 alveolar macrophage Anatomy 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 239000006053 animal diet Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000002402 anti-lipaemic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000005135 aryl sulfinyl group Chemical group 0.000 description 1
- 125000005421 aryl sulfonamido group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 108010014210 axokine Proteins 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000001601 blood-air barrier Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004781 brain capillary Anatomy 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- RMRJXGBAOAMLHD-CTAPUXPBSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-CTAPUXPBSA-N 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229960001058 bupropion Drugs 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000013130 cardiovascular surgery Methods 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 229930007646 carveol Natural products 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000027448 caveolin-mediated endocytosis Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000015861 cell surface binding Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- LNAMMBFJMYMQTO-FNEBRGMMSA-N chloroform;(1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].ClC(Cl)Cl.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 LNAMMBFJMYMQTO-FNEBRGMMSA-N 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- BHYOQNUELFTYRT-DPAQBDIFSA-N cholesterol sulfate Chemical compound C1C=C2C[C@@H](OS(O)(=O)=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 BHYOQNUELFTYRT-DPAQBDIFSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000006395 clathrin-mediated endocytosis Effects 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 1
- NLCKLZIHJQEMCU-UHFFFAOYSA-N cyano prop-2-enoate Chemical class C=CC(=O)OC#N NLCKLZIHJQEMCU-UHFFFAOYSA-N 0.000 description 1
- WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical compound C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004983 dialkoxyalkyl group Chemical group 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- CRVGKGJPQYZRPT-UHFFFAOYSA-N diethylamino acetate Chemical compound CCN(CC)OC(C)=O CRVGKGJPQYZRPT-UHFFFAOYSA-N 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 229950001279 elafibranor Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229950000234 emricasan Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 230000008497 endothelial barrier function Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000019439 energy homeostasis Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 230000028023 exocytosis Effects 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 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 1
- 239000011521 glass Substances 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 102000035122 glycosylated proteins Human genes 0.000 description 1
- 108091005608 glycosylated proteins Proteins 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 210000003547 hepatic macrophage Anatomy 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000005241 heteroarylamino group Chemical group 0.000 description 1
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- LNCPIMCVTKXXOY-UHFFFAOYSA-N hexyl 2-methylprop-2-enoate Chemical compound CCCCCCOC(=O)C(C)=C LNCPIMCVTKXXOY-UHFFFAOYSA-N 0.000 description 1
- LNMQRPPRQDGUDR-UHFFFAOYSA-N hexyl prop-2-enoate Chemical compound CCCCCCOC(=O)C=C LNMQRPPRQDGUDR-UHFFFAOYSA-N 0.000 description 1
- 229950007035 homocamfin Drugs 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical group O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229950011269 isaglidole Drugs 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 229910000833 kovar Inorganic materials 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000001510 limonene Nutrition 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- XTTZERNUQAFMOF-QMMMGPOBSA-N lorcaserin Chemical compound C[C@H]1CNCCC2=CC=C(Cl)C=C12 XTTZERNUQAFMOF-QMMMGPOBSA-N 0.000 description 1
- 229960005060 lorcaserin Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 description 1
- 229960002137 melagatran Drugs 0.000 description 1
- 230000008384 membrane barrier Effects 0.000 description 1
- 230000009061 membrane transport Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 1
- CJRHLSZJEFJDLA-UHFFFAOYSA-N methyl 5-bromo-2-iodobenzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1I CJRHLSZJEFJDLA-UHFFFAOYSA-N 0.000 description 1
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
- 229940012189 methyl orange Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 108091066112 miR-122-1 stem-loop Proteins 0.000 description 1
- 108091057488 miR-122-2 stem-loop Proteins 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- GICWIDZXWJGTCI-UHFFFAOYSA-I molybdenum pentachloride Chemical compound Cl[Mo](Cl)(Cl)(Cl)Cl GICWIDZXWJGTCI-UHFFFAOYSA-I 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 210000002864 mononuclear phagocyte Anatomy 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 229940051875 mucins Drugs 0.000 description 1
- 229950001135 muraglitazar Drugs 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 229940028444 muse Drugs 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- ZLVARELBORDLAV-UHFFFAOYSA-N n-(4,5-dihydro-1h-imidazol-2-yl)-4-fluoro-1,3-dihydroisoindol-2-amine Chemical compound C1C=2C(F)=CC=CC=2CN1NC1=NCCN1 ZLVARELBORDLAV-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- UMWKZHPREXJQGR-XOSAIJSUSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]decanamide Chemical compound CCCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO UMWKZHPREXJQGR-XOSAIJSUSA-N 0.000 description 1
- VHYYJWLKCODCNM-OIMNJJJWSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]heptanamide Chemical compound CCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO VHYYJWLKCODCNM-OIMNJJJWSA-N 0.000 description 1
- GCRLIVCNZWDCDE-SJXGUFTOSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]nonanamide Chemical compound CCCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO GCRLIVCNZWDCDE-SJXGUFTOSA-N 0.000 description 1
- SBWGZAXBCCNRTM-CTHBEMJXSA-N n-methyl-n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]octanamide Chemical compound CCCCCCCC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SBWGZAXBCCNRTM-CTHBEMJXSA-N 0.000 description 1
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical class [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 239000002159 nanocrystal Substances 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 229940020452 neupro Drugs 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- LBQAJLBSGOBDQF-UHFFFAOYSA-N nitro azanylidynemethanesulfonate Chemical compound [O-][N+](=O)OS(=O)(=O)C#N LBQAJLBSGOBDQF-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- YLACRFYIUQZNIV-UHFFFAOYSA-N o-(2,4-dinitrophenyl)hydroxylamine Chemical compound NOC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O YLACRFYIUQZNIV-UHFFFAOYSA-N 0.000 description 1
- 238000013116 obese mouse model Methods 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- NZIDBRBFGPQCRY-UHFFFAOYSA-N octyl 2-methylprop-2-enoate Chemical compound CCCCCCCCOC(=O)C(C)=C NZIDBRBFGPQCRY-UHFFFAOYSA-N 0.000 description 1
- 229940065472 octyl acrylate Drugs 0.000 description 1
- ANISOHQJBAQUQP-UHFFFAOYSA-N octyl prop-2-enoate Chemical compound CCCCCCCCOC(=O)C=C ANISOHQJBAQUQP-UHFFFAOYSA-N 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- RPQRDASANLAFCM-UHFFFAOYSA-N oxiran-2-ylmethyl prop-2-enoate Chemical compound C=CC(=O)OCC1CO1 RPQRDASANLAFCM-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 229940098695 palmitic acid Drugs 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 125000005499 phosphonyl group Chemical group 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000004560 pineal gland Anatomy 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920001553 poly(ethylene glycol)-block-polylactide methyl ether Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- ZIFYBJMSVYAEIJ-UHFFFAOYSA-N propane-1,3-diol;pyridin-3-ylboronic acid Chemical compound OCCCO.OB(O)C1=CC=CN=C1 ZIFYBJMSVYAEIJ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229940035613 prozac Drugs 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000012383 pulmonary drug delivery Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical class SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000013464 silicone adhesive Substances 0.000 description 1
- LCHWKMAWSZDQRD-UHFFFAOYSA-N silylformonitrile Chemical class [SiH3]C#N LCHWKMAWSZDQRD-UHFFFAOYSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000004895 subcellular structure Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940053209 suboxone Drugs 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 108010048573 taspoglutide Proteins 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124598 therapeutic candidate Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical class CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000003041 virtual screening Methods 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/01—Hydrocarbons
- A61K31/015—Hydrocarbons carbocyclic
-
- 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
- A61K31/13—Amines
- A61K31/131—Amines acyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
-
- 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)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Biochemistry (AREA)
- Cardiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
调节视黄酸受体样孤儿受体(ROR)和相关疾病的化合物、组合物和方法。公开了用于治疗或预防代谢性疾病、肝脏失调或疾病例如NASH、免疫紊乱、中枢神经系统失调，或癌症的方法。
Description
技术领域
本发明要求保护视黄酸受体相关的孤儿受体(ROR)例如RORα、RORβ或RORγ的小分子调节剂。本发明提供了ROR调节剂在癌症、肝病(例如NASH)、血脂异常、自身免疫和代谢性疾病中的用途。
背景技术
II型核受体蛋白是激素调节的转录因子。视黄酸受体相关的孤儿受体(ROR)是II型核受体，其存在于隔离DNA的细胞核中。存在三种主要的ROR亚型RORα、RORβ或RORγ，并根据与视黄酸受体的序列相似性鉴定了几种变体。ROR亚型的主要区别在于表达模式。RORα在肝、肌肉、皮肤、脂肪和免疫细胞等许多组织中表达。RORβ在脑、视网膜和松果体中特异性表达。RORγ与RORα具有相似的表达模式，但在胸腺中的表达水平很高。主要的ROR亚型具有一个共同的结构基序，该基序由包含激活功能1(AF-1)的N末端A/B结构域、也称为DNA结合结构域(DBD)的C结构域、可变接头结构域D和也称为配体结合结构域(LBD)的C末端E结构域组成，其中C末端E结构域具有配体依赖性激活功能2(AF-2)。DBD将ROR锚定到特定的DNA序列，即ROR响应元件(RORE)。调节剂与LBD的结合会引起构象变化，从而导致转录蛋白与AF-1和AF-2结合。一些调节剂通过诱导共阻遏蛋白与ROR的结合来降低RORE处的转录。或者，其他调节剂诱导共激活蛋白募集到ROR，导致转录增强。基于ROR调控的基因，这些蛋白质在昼夜节律、新陈代谢、免疫功能、发育和脑功能中发挥作用。[Kojetin,DJ and Burris,TP.Nature Reviews Drug Discovery(2014)13:197–216]
ROR与癌症的发生、发展和严重程度有关[Qiu和Wang。Retinoic Acid Receptor-Related Orphan Receptorγt(RORγt)Agonists as Potential Small MoleculeTherapeutics for Cancer Immunotherapy.Journal of Medicinal Chemistry(2018)]。缺乏RORγ的小鼠会迅速发展成转移性T细胞淋巴瘤。较高的RORγ水平与乳腺癌的预后改善相关。几种癌症显示出RORα表达降低，例如乳腺癌、结直肠癌和前列腺癌。RORα表达的恢复抑制癌症的增殖和转移。[Cook,DN,Kang HS,和Jetten,AM.Nuclear Receptor Research(2015)2]此外，用ROR调节剂治疗可诱导癌细胞凋亡[Wand,Y等人PloS ONE(2012)7:e34921]。因此，可以考虑将ROR调节剂作为单一疗法或组合疗法用于癌症化疗。
分泌白介素17(IL-17)的CD4+T辅助细胞称为Th17细胞。Th17细胞在宿主防御细菌、真菌、寄生虫和病毒感染中具有生物学作用。Th17细胞的失调与几种免疫系统紊乱有关。Th17细胞参与风湿性疾病(牛皮癣、关节炎、全身性硬化症和系统性红斑狼疮)、自身免疫性疾病(多发性硬化症、自身免疫性心肌炎、糖尿病和自身免疫性甲状腺炎)、哮喘、过敏性疾病以及其他免疫介导的疾病，例如炎性肠病和牙周病。Th17细胞也参与癌症的存活、增殖和存活。[Tesmer,LA等人，Immunological Reviews(2008)223:87-113]已经显示靶向ROR的化合物可调节Th17水平和IL-17分泌，[Solt,LA等人，Nature(2011):472:491-494]，因此考虑将这类化合物用于治疗Th17相关疾病和失调。
ROR调节能量稳态，包括脂质和葡萄糖代谢。缺乏ROR的小鼠(staggerer)的增重、肥胖和肝脂肪变性降低，且胰岛素敏感性和脂质代谢/葡萄糖代谢有所改善，这表明它们可抵抗高脂饮食(HFD)诱导的代谢综合征。相反，腺病毒介导的肝脏中ROR的过度表达也降低了高脂饮食喂养小鼠的甘油三酸酯水平。RORα的Cistrome数据显示，在肝脏中，RORα被募集到对葡萄糖稳态和脂质代谢很重要的几个基因中的RORE，这表明RORα通过在其调节区域结合RORE来积极调节这些代谢基因的转录。RORα在胰岛素敏感性调节中的作用得到一项研究的支持，该研究表明RORα中的单核苷酸多态性(rs7164773)与墨西哥Mestizo人群中2型糖尿病的风险增加之间存在关联。与对照相比，缺乏RORγ亚型的小鼠具有改善的胰岛素敏感性。研究表明，RORγ的表达水平在人肥胖患者中与肥胖和胰岛素抵抗呈正相关，这些研究支持了RORγ在调节胰岛素抵抗中的作用。[Cook,DN,Kang HS,和Jetten,AM.NuclearReceptor Research(2015)2]
将有利的是提供ROR调节剂和治疗方法，特别是治疗代谢性疾病、糖尿病、血脂异常和肝病的方法。本发明提供了这样的药剂、组合物和方法。
发明内容
在一个实施方案中，公开了用于治疗与ROR核受体有关的病症，特别是癌症、与Th17相关的疾病或肝脏疾病的化合物、方法和组合物。
在一个实施方案中，提供了用于调节ROR的生物活性的方法。该方法包括使ROR与有效量的如下所示的式(A)化合物接触，其中该化合物是包含ROR亚家族的任何亚型(包括RORα、RORβ或RORγ)的任何序列变体的受体的激动剂或活化剂，或者是阻遏剂、反向激动剂或拮抗剂。
本发明提供了用于实施本发明方法的新型化合物。本发明提供了用于进行本发明方法的立体异构体和多晶型。本发明提供了用于实施本发明方法的盐或前药制剂。
在各种实施方案中，提供了具有有效的式(A)化合物的药物组合物和制剂以治疗与ROR核受体有关的病症。
本发明提供了包含本发明的化合物和一种或多种其他药物的药物组合。
参考以下详细描述将更好地理解本发明。
附图说明
图1是显示化合物1如何在WT RORE的情况下诱导RORα调节的荧光素酶表达，但是当RORE突变时不具有活性的图。数据以相对萤光素酶活性对浓度的形式表示，误差条＝SD。与DMSO相比*P<0.05。
图2是显示化合物1如何特异性增加Huh-7细胞的miR-122分泌的图，以Huh7培养基中的相对microRNA水平对DMSO对照和化合物1(1μM)的形式表示。数据以误差条＝SD表示。**P<0.01。
图3A-B是显示化合物1如何调节人外周单核细胞(PBMC)中的Th17群体的图。图3A显示了如何通过存活/死亡可固定的水生死细胞染色确定CD4+T细胞的存活力，以在整个CD4+Th17细胞群体中的％存活力表示。图3B显示了通过在CD3+/CD4+/CD45RA-/CXCR3-/CCR4+CXCR5-/CCR6+细胞上圈门(gating)确定的CD4+Th17细胞的总百分比组成(以％Th17细胞表示)。这些结果表明，化合物1在刺激条件下选择性降低了CD4+Th17群体。
图4A-E是显示化合物1如何增加小鼠(n＝3)中RORα靶基因–miR-122和Gpase6的表达的图。图4A显示了在7天内测得的miR-122水平的血浆水平，而图4B显示了其肝脏水平。图4C显示了在7天内测量的miR-122和RORα靶基因(分别为Aldoa和Gpase6)和miR-122前体的mRNA水平。数据显示，分泌的miR-122进入周围组织。图4D和4E显示了在7天内测量的骨骼肌(4D)和白色脂肪组织(“WAT”)(4E)中的miR-122水平。数据显示，用化合物1处理后，miR-18和miR-126不受影响。数据以误差条＝SD表示。相比于盐水，*P<0.05，**P<0.01，***P<0.001。白色条为对照(盐水)，红色条为第1天的结果，粉红色条为第3天的结果，紫色条为第7天的结果。
图5A-C是显示化合物1(Cmpd1)处理通过miR-122活性降低高脂喂养的C57BL/6小鼠的体重并增加能量消耗的图线。图5A显示了处理之前(蓝色)和处理3周之后(红色)的体重(g)变化。图5B显示了在最终时间点血浆中相对miR-122水平的qRT-PCR分析。图5C是显示处理3周后β-羟基丁酸酯血浆水平(以nM计)的比色定量的图线。图5D是通过肝脏切片的H&E染色可视化的代表性脂质蓄积的照片。N＝5。数据以误差条＝SD表示。*P<0.05，**P<0.01，***P<0.001。
图5D是通过肝脏切片的H&E染色可视化的代表性脂质积聚的照片。使用antagomir静默内源性microRNA。antagomir是具有某些修饰的小型合成RNA，其与特定的miRNA完美互补，并阻止其与其mRNA靶标结合。在上面的两张照片中，将antagomir用作阴性对照(模拟对照)，称为antagomir-对照(中国RiboBio公司)，包括使用化合物1(右侧)和不使用化合物1(左侧)。在下面的两张照片中，使用了一个与miR-122基本互补的antagomir(antagomiR-122)，包括使用化合物1(右侧)和不使用化合物1(左侧)。照片显示当施用化合物1时脂质滴积聚减少。
图6A-C是显示在Sgp130FC小鼠(n＝3)中施用化合物1增加miR-122表达并降低肝和肌肉甘油三酯水平的图。向Sgp130FC小鼠注射(ip)化合物1四个星期(7.5mg/kg，每周两次)。图6A-6B显示了用盐水(作为对照)和化合物1处理4周后血浆(6A)和肝脏(6B)中miR-122水平的qRT-PCR分析。MicroRNA-18用作阴性对照，在用化合物1处理后，其血浆和肝脏水平未受影响。与在miR-122上看到的显著效果相比，在图6A中对该microRNA看到的效果不显著。图6C是显示在施用盐水(作为对照)和化合物1后肝脏中甘油三酯(TG)的比色定量(mg/g)的图。数据以误差条＝S.D.表示。*P<0.05。
图6D是通过注射盐水(左侧)和注射化合物1(右侧)的小鼠的肝脏切片的H&E染色观察到的代表性脂质积聚的照片。照片显示当施用化合物1时脂质滴积聚减少。
图6E是显示骨骼肌中甘油三酯的比色定量(TG，mg/g)的图。数据以误差条＝SD表示。*P<0.05。
图7A和图7B分别示出了在用化合物1或盐水处理的小鼠中从血浆和肝脏提取的miR-122的qRT-PCR分析的结果。图7C显示了从小鼠肝脏提取的Fgf21和G6pc以及RORα靶基因pri-miR-122mRNA和pre-miR-122mRNA的qRT-PCR分析。图7D是示出了对施用盐水或化合物1的小鼠的肝脏甘油三酯(TG)水平(mg/dL)的定量的图。
图8A显示了C57BL/6小鼠的体重，该C57BL/6小鼠用高脂饮食(HFD)喂养6周，并每周3次注射15mg/kg化合物1(方块)或对照(盐水+DMSO)(菱形)，注射3周(n＝6)。图8B是用化合物1或对照处理的小鼠的肝脏(用H&E(血红素/曙红Y)染色)的显微照片。图8C是显示实验结束时测得的肝脏/体重比(％)的图。
图9A-E是显示当向C57BL/6小鼠施用化合物1或对照(盐水+DMSO)时，小鼠模型在24小时内的代谢输出的变化的图。图9A比较了溶媒vs化合物1处理的小鼠中的体积O2(1/d/kg0.75)。图9B比较了溶媒vs化合物1处理的小鼠中的体积CO2(1/d/kg0.75)。图9C比较了溶媒vs化合物1处理的小鼠中的总能量消耗(Kcal/h/kg0.75)。图9D比较了溶媒vs化合物1处理的小鼠中的脂肪氧化(g/d/kg0.75)。图9E比较了溶媒vs化合物1处理的小鼠中的碳水化合物氧化(g/d/kg0.75)。有效质量由0.75的幂计算。数据是每组8只小鼠的平均值±SEM。
图10是一个图，显示了在喂食HFD 6周并注射15mg/kg化合物1(红色)的C57BL/6小鼠vs喂食HFD的用生理盐水处理的(蓝色)小鼠和正常饮食的小鼠(对照ND，绿色)中，注射胰岛素(88个单位)后的葡萄糖水平(％/分钟)；分钟表示注射胰岛素后的时间。n.s.＝不显著。图11A-D是显示C57BL/6小鼠的肝损伤的各种标记的图，所述C57BL/6小鼠喂食动脉粥样化饮食3周(诱导纤维化)并每周3次注射15mg/kg化合物1(或盐水+DMSO)3.5周(n＝8)。对于未处理(灰色柱)和处理(黑色柱)队列，从血浆(图11A)和肝脏(图11B)提取的miR-122的qRT-PCR分析。血浆和肝脏中的miR-93和miR-18分别用作阴性对照。图11C是显示实验结束时测得的ALT和AST血浆水平的图。图11D是显示从小鼠肝脏提取的纤维化中涉及的基因和RORα靶基因(Fgf21)的mRNA的qRT-PCR分析的图。将血浆中的microRNA水平标准化至掺入的秀丽隐杆线虫miR-39；将组织中的microRNA水平标准化至RNU6。mRNA水平标准化至HPRT。数据以误差条＝SD表示。*P<.05，**P<.01。***P<.001，****P<0.0001。
图12A显示了从经盐水或经化合物1处理的小鼠获取的H&E、CD3和F4/80染色的肝脏的代表性显微照片；比例尺代表10μm。图12B是示出使用ImageJ对阳性染色的F4/80区域进行定量的图。
图13A和C是取自经盐水或经化合物1处理的小鼠的Masson三色(M.T.)染色和α-SMA染色的肝脏的显微照片；比例尺代表10μm。图13B和D是示出使用ImageJ(％)对阳性染色区域进行定量的图。M.T.染色显示在图13B中，而SMA染色显示在图13D中。
具体实施方式
本文所述的式(A)的化合物调节ROR靶基因在肝细胞(特别是与代谢和肝病有关的肝细胞)中的表达。因此，这些化合物可用于治疗或预防肝脏疾病，例如但不限于肝硬化、肝纤维化、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、肝缺血再灌注损伤、原发性胆汁性肝硬化(PBC)和肝炎，包括病毒性和酒精性肝炎。这些化合物可用于治疗或预防代谢疾病，例如但不限于血脂异常、肥胖、胰岛素抗药性或糖尿病。
本文所述的化合物调节人外周单核细胞培养物中Th17细胞的种群。因此，这些化合物可用于治疗或预防与Th17有关的病况或疾病，例如但不限于风湿性疾病(牛皮癣、关节炎、系统性硬化症和系统性红斑狼疮)、自身免疫性疾病(多发性硬化症、自身免疫性心肌炎、糖尿病和自身免疫性甲状腺炎)、哮喘、过敏性疾病以及其他免疫介导的疾病，例如炎症性肠病和牙周病。
本文所述的化合物分别显示出对淋巴细胞白血病和肝癌细胞系CCRF-CEM和Huh-7的抑制活性。因此，这些化合物可用于治疗或预防癌症和相关疾病或病症。更具体地，癌症可包括前列腺癌、结肠癌、乳腺癌、肺癌等。
还公开了药物制剂，其包含一种或多种本文所述的化合物，以及药学上可接受的载体或赋形剂。在一个实施方案中，制剂包括至少一种本文所述的化合物和至少一种其他治疗剂。
参考以下定义将更好地理解本发明：
I.定义
术语“独立地”在本文中用于表示独立应用的变量因应用情况而独立变化。因此，在诸如其中R”“独立地为碳或氮”的R”XYR”的化合物中，两个R”可以都是碳，两个R”可以都是氮，或者一个R”可以是碳，另一个R”可以是氮。
术语“调节剂”包括拮抗剂、变构抑制剂、激动剂和部分激动剂。某些调节剂可以关闭ROR表达(直接拮抗剂和变构抑制剂，以及部分激动剂以剂量依赖性方式)，而其他调节剂(激动剂和部分激动剂，后者以剂量依赖性方式)可以增加ROR表达。
如本文所用，术语“对映异构体纯的”是指包含至少约95％，优选约97％、98％、99％或100％的该化合物的单一对映异构体的化合物组合物。
如本文所用，术语“基本上不含”或“基本上不存在”是指包含至少85％至90％重量，优选95％至98％重量，甚至更优选地，99％至100％重量的该化合物的指定对映异构体的化合物组合物。在一个优选的实施方案中，本文所述的化合物基本上不含对映异构体。
类似地，术语“分离的”是指这样的化合物组合物，其包含至少85％至90％重量，优选95％至98％重量，甚至更优选地，99％至100％重量的化合物，其余包含其他化学物质或对映异构体。
除非另有说明，否则本文所用的术语“烷基”是指饱和的直链、支链或环状伯、仲或叔烃，包括取代和未取代的烷基。烷基可以任选地被不另外干扰反应或者提供该方法的改进的任意部分取代，包括但不限于卤素、卤代烷基、羟基、羧基、酰基、芳基、酰氧基、氨基、酰氨基、羧基衍生物、烷基氨基、二烷基氨基、芳基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、硫醇、亚胺、磺酰基、硫烷基、亚磺酰基、氨磺酰基、酯、羧酸、酰胺、膦酰基、氧膦基、磷酰基、膦、硫酯、硫醚、酰卤、酸酐、肟、肼、氨基甲酸酯、膦酸、膦酸酯，其是未受保护的或视需要受到保护的，如本领域技术人员已知的，例如如Greene等人，Protective Groups in OrganicSynthesis，John Wiley and Sons，第二版，1991所教导的，在此通过引用并入。具体包括CF3和CH2CF3。当烷基部分在两个末端都被取代时，它是“亚烷基”部分，例如亚甲基部分，并且其意在包含在本文中。
在本文中，每当使用术语C(烷基范围)时，该术语独立地包括该类的每个成员，如同具体地、单独地列出一样。术语“烷基”包括C1-22烷基部分，术语“低级烷基”包括C1-6烷基部分。本领域普通技术人员应理解，相关的烷基基团通过用后缀“-基(-yl)”代替后缀“-烷烃(-ane)”来命名。
如本文所用，“桥连烷基(bridged alkyl)”是指双环或三环烷烃，例如，2:1:1双环己烷。
如本文所用，“螺烷基(spiro alkyl)”是指连接在单个(季)碳原子上的两个环。
术语“烯基”是指不饱和的烃基，为直链或支链，只要它含有一个或多个双键即可。本文公开的烯基基团可以任选地被对反应过程无不利影响的任意部分取代，包括但不限于对烷基部分上的取代基所描述的那些。烯基基团的非限制性实例包括乙烯、甲基乙烯、异亚丙基、1,2-乙烷-二基、1,1-乙烷-二基、1,3-丙烷-二基、1,2-丙烷-二基、1,3-丁烷-二基和1,4-丁烷-二基。
术语“炔基”是指不饱和的无环烃基，为直链或支链，只要它含有一个或多个三键即可。炔基基团可以任选地被对反应过程无不利影响的任意部分取代，包括但不限于上述对烷基部分描述的那些。合适的炔基基团的非限制性实例包括乙炔基、丙炔基、羟丙炔基、丁炔-1-基、丁炔-2-基、戊炔-1-基、戊炔-2-基、4-甲氧基戊炔-2-基、3-甲基丁炔-1-基、己炔-1-基、己炔-2-基和己炔-3-基、3,3-二甲基丁炔-1-基。
术语“烷基氨基”或“芳基氨基”分别指具有一个或两个烷基或芳基取代基的氨基。
如本文所用，术语“脂肪醇”是指在链中具有4至26个碳，优选在链中具有8至26个碳，最优选在链中具有10至22个碳的直链伯醇。精确的链长随来源而变化。代表性的脂肪醇包括月桂基、硬脂基和油烯基醇。它们是无色油状液体(对于较小的碳数)或蜡状固体，但是不纯的样品可能会显示黄色。脂肪醇通常具有偶数个碳原子，并且在末端碳上连接有一个醇基(-OH)。有些是不饱和的，有些是支链的。它们在工业中被广泛使用。与脂肪酸一样，它们通常用分子中的碳原子数来表示，例如“C12醇”，即具有12个碳的醇，例如十二烷醇。
除非另外定义，否则本文所用的术语“受保护的”是指加到氧、氮或磷原子以防止其进一步反应或用于其它目的的基团。多种氧和氮保护基团是有机合成领域技术人员已知的，描述于例如Greene等人，Protective Groups in Organic Synthesis，同上。
单独或组合使用的术语“芳基”是指含有一个、两个或三个环的碳环芳族体系，其中这些环可以以悬垂方式连接在一起或者可以稠合。芳基的非限制性实例包括苯基、联苯基或萘基，或从芳环除去氢后保留的其它芳族基团。术语芳基包括取代和未取代的部分。芳基基团可以任选地被对过程无不利影响的任意部分取代，包括但不限于上述对烷基部分所描述的那些。取代的芳基的非限制性实例包括杂芳基氨基、N-芳基-N-烷基氨基、N-杂芳基氨基-N-烷基氨基、杂芳烷氧基、芳基氨基、芳烷基氨基、芳硫基、单芳基酰氨磺酰基、芳基亚磺酰氨基、二芳基酰氨磺酰基、单芳基酰氨基磺酰基、芳基亚磺酰基、芳基磺酰基、杂芳基硫基、杂芳基亚磺酰基、杂芳基磺酰基、芳酰基、杂芳酰基、芳烷酰基、杂芳烷酰基、羟基芳烷基、羟基杂芳烷基、卤代烷氧基烷基、芳基、芳烷基、芳氧基、芳烷氧基(arylkoxy)、芳氧基烷基、饱和杂环基、部分饱和的杂环基、杂芳基、杂芳氧基、杂芳氧基烷基、芳烷基、杂芳基烷基、芳基烯基和杂芳基烯基、芳烷氧羰基(carboaralkoxy)。
术语“烷芳基”或“烷基芳基”是指具有芳基取代基的烷基。术语“芳烷基”或“芳基烷基”是指具有烷基取代基的芳基。
本文所用的术语“卤素”包括氯、溴、碘和氟。
术语“酰基”是指一种羧酸酯，其中酯基团的非羰基部分选自由以下组成的组：直链、支链或环状烷基或低级烷基，烷氧基烷基(包括但不限于甲氧基甲基)，芳烷基(包括但不限于苄基)，芳氧基烷基(如苯氧基甲基)，芳基(包括但不限于苯基)，其任选地被以下取代：卤素(F、Cl、Br或I)，烷基(包括但不限于C1、C2、C3和C4)或烷氧基(包括但不限于C1、C2、C3和C4)，磺酸酯(如烷基或芳烷基磺酰基，包括但不限于甲磺酰基)，单、二或三磷酸酯，三苯甲基或单甲氧基三苯甲基，取代的苄基，三烷基甲硅烷基(例如二甲基-叔丁基甲硅烷基)或二苯基甲基甲硅烷基。酯中的芳基基团最佳地包含苯基基团。术语“低级酰基”是指这样一种酰基基团，其中非羰基部分是低级烷基。
术语“烷氧基”和“烷氧基烷基”包括具有烷基部分的直链或支链含氧基团，例如甲氧基。术语“烷氧基烷基”还包括具有一个或多个与烷基连接的烷氧基的烷基，即，形成单烷氧基烷基和二烷氧基烷基。“烷氧基”基团可以进一步被一个或多个卤原子取代，例如氟、氯或溴，以提供“卤代烷氧基”基团。这些基团的实例包括氟甲氧基、氯甲氧基、三氟甲氧基、二氟甲氧基、三氟乙氧基、氟乙氧基、四氟乙氧基、五氟乙氧基和氟丙氧基。
术语“烷基氨基”表示分别含有一个或两个与氨基连接的烷基的“单烷基氨基”和“二烷基氨基”。术语芳基氨基表示分别含有一个或两个与氨基基团连接的芳基基团的“单芳基氨基”和“二芳基氨基”。术语“芳烷基氨基”包括与氨基基团连接的芳烷基基团。术语芳烷基氨基表示分别含有一个或两个与氨基连接的芳烷基的“单芳烷基氨基”和“二芳烷基氨基”。术语芳烷基氨基还表示含有与氨基基团连接的一个芳烷基基团和一个烷基基团的“单芳烷基单烷基氨基”。
如本文所用的术语“杂原子”是指氧、硫、氮和磷。
如本文所用的术语“杂芳基”或“杂芳族”是指芳环中包含至少一个硫、氧、氮或磷的芳族化合物。
术语“杂环”、“杂环基”和环杂烷基是指非芳族环状基团，其中在环中存在至少一个杂原子，例如氧、硫、氮或磷。
杂芳基和杂环基团的非限制性实例包括呋喃基(furyl)、呋喃基(furanyl)、吡啶基、嘧啶基、噻吩基、异噻唑基、咪唑基、四唑基、吡嗪基、苯并呋喃基、苯并噻吩基、喹啉基、异喹啉基、苯并噻吩基、异苯并呋喃基、吡唑基、吲哚基、异吲哚基、苯并咪唑基、嘌呤基、咔唑基、噁唑基、噻唑基、异噻唑基、1,2,4-噻二唑基、异噁唑基、吡咯基、喹唑啉基、噌啉基(cinnolinyl)、酞嗪基、黄嘌呤基(xanthinyl)、次黄嘌呤基(hypoxanthinyl)、噻吩、呋喃、吡咯、异吡咯、吡唑、咪唑、1,2,3-三唑、1,2,4-三唑、噁唑、异噁唑、噻唑、异噻唑、嘧啶或哒嗪和蝶啶基、氮丙啶、噻唑、异噻唑、1,2,3-噁二唑、噻嗪、吡啶、吡嗪、哌嗪、吡咯烷、氧氮杂环丙烷(oxazirane)、吩嗪、吩噻嗪、吗啉基、吡唑基、哒嗪基、吡嗪基、喹喔啉基、黄嘌呤基、次黄嘌呤基、蝶啶基、5-氮杂胞苷基(5-azacytidinyl)、5-氮杂尿嘧啶基(5-azauracilyl)、三唑并吡啶基、咪唑并吡啶基、吡咯并嘧啶基、吡唑并嘧啶基、腺嘌呤、N6-烷基嘌呤、N6-苄基嘌呤、N6-卤代嘌呤、N6-乙烯基嘌呤(vinypurine)、N6-炔嘌呤、N6-酰基嘌呤、N6-羟烷基嘌呤、N6-硫代烷基嘌呤、胸腺嘧啶、胞嘧啶、6-氮杂嘧啶、2-巯基嘧啶、尿嘧啶、N5-烷基嘧啶、N5-苄基嘧啶、N5-卤代嘧啶、N5-乙烯基嘧啶、N5-炔嘧啶、N5-酰基嘧啶、N5-羟烷基嘌呤和N6-硫代烷基嘌呤和异噁唑基。杂芳族基团可以任选地被取代，如以上对于芳基所述。杂环或杂芳族基团可任选地被一个或多个选自卤素、卤代烷基、烷基、烷氧基、羟基、羧基衍生物、酰氨基、氨基、烷基氨基和二烷基氨基的取代基取代。杂芳族化合物可根据需要部分或完全氢化。作为非限制性实例，可以使用二氢吡啶代替吡啶。可以根据需要或期望保护杂环或杂芳基上的官能氧和氮基团。合适的保护基团是本领域技术人员熟知的，包括三甲基甲硅烷基、二甲基己基甲硅烷基、叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基、三苯甲基或取代的三苯甲基、烷基、酰基如乙酰基和丙酰基、甲磺酰基和对甲苯磺酰基。杂环或杂芳族基团可以被对反应无不利影响的任意部分取代，包括但不限于上述对于芳基所描述的那些。
如本文所用的术语“宿主”是指病毒可以在其中复制的单细胞或多细胞生物体，包括但不限于细胞系和动物，并且优选是人。或者，宿主可以携带病毒基因组的一部分，其复制或功能可以被本发明的化合物改变。术语宿主特别是指感染的细胞，用全部或部分病毒基因组转染的细胞，和动物，特别是灵长类动物(包括但不限于黑猩猩)和人类。在本发明的大多数动物应用中，宿主是人类。然而，在某些适应症中，本发明清楚地考虑兽医应用(例如用于治疗黑猩猩)。
术语“肽”是指含有2至100个氨基酸的天然或合成化合物，这些氨基酸通过一个氨基酸的羧基与另一个氨基酸的氨基连接。
在整个说明书中使用术语“药学上可接受的盐或前药”来描述化合物的任意药学上可接受的形式(例如酯)，在向患者施用后，其提供该化合物。药学上可接受的盐包括衍生自药学上可接受的无机碱和无机酸或有机碱和有机酸的盐。合适的盐包括衍生自碱金属如钾和钠、碱土金属如钙和镁以及制药领域熟知的许多其它酸的盐。
药学上可接受的前药是指在宿主中被代谢(例如被水解或氧化)以形成本发明化合物的化合物。前药的典型实例包括在活性化合物的功能部分上具有生物学上不稳定的保护基团的化合物。前药包括可被氧化、还原、胺化、脱氨基、羟基化、脱羟基化、水解、脱水、烷基化、脱烷基化、酰化、脱酰化、磷酸化或去磷酸化以产生活性化合物的化合物。本发明化合物的前药形式可以具有抗病毒活性，可以被代谢形成表现出这种活性的化合物，或二者兼具。
以下参考文献中描述了磷酸盐/膦酸酯前药的非限制性实例：Ho,D.H.W.(1973)"Distribution of Kinase and deaminase of 1-beta-D-arabinofuranosylcytosine intissues of man and muse."Cancer Res.33,2816-2820；Holy,A.(1993)Isopolarphosphorous-modified nucleotide analogues,"In:De Clercq(Ed.),Advances inAntiviral Drug Design,Vol.I,JAI Press,pp.179-231；Hong,C.I.,Nechaev,A.,andWest,C.R.(1979a)"Synthesis and antitumor activity of 1-beta-D-arabino-furanosylcytosine conjugates of cortisol and cortisone."Bicohem.Biophys.Rs.Commun.88,1223-1229；Hong,C.I.,Nechaev,A.,Kirisits,A.J.Buchheit,D.J.and West,C.R.(1980)"Nucleoside conjugates as potentialantitumor agents.3.Synthesis and antitumor activity of 1-(beta-D-arabinofuranosyl)cytosine conjugates of corticosteroids and selectedlipophilic alcohols."J.Med.Chem.28,171-177；Hosteller,K.Y.,Stuhmiller,L.M.,Lenting,H.B.M.van den Bosch,H.and Richman J.Biol.Chem.265,6112-6117；Hosteller,K.Y.,Carson,D.A.and Richman,D.D.(1991)；"Phosphatidylazidothymidine:mechanism of antiretroviral action in CEM cells."J.Biol Chem.266,11714-11717；Hosteller,K.Y.,Korba,B.Sridhar,C.,Gardener,M.(1994a)"Antiviral activity ofphosphatidyl-dideoxycytidine in hepatitis B-infected cells and enhancedhepatic uptake in mice."Antiviral Res.24,59-67；Hosteller,K.Y.,Richman,D.D.,Sridhar.C.N.Felgner,P.L.Felgner,J.,Ricci,J.,Gardener,M.F.Selleseth,D.W.andEllis,M.N.(1994b)"Phosphatidylazidothymidine and phosphatidyl-ddC:Assessmentof uptake in mouse lymphoid tissues and antiviral activities in humanimmunodeficiency virus-infected cells and in rauscher leukemia virus-infectedmice."Antimicrobial Agents Chemother.38,2792-2797；Hunston,R.N.,Jones,A.A.McGuigan,C.,Walker,R.T.,Balzarini,J.,and DeClercq,E.(1984)"Synthesis andbiological properties of some cyclic phosphotriesters derived from 2'-deoxy-5-flourouridine."J.Med.Chem.27,440-444；Ji,Y.H.,Moog,C.,Schmitt,G.,Bischoff,P.and Luu,B.(1990)；"Monophosphoric acid esters of 7-.beta.-hydroxycholesteroland of pyrimidine nucleoside as potential antitumor agents:synthesis andpreliminary evaluation of antitumor activity."J.Med.Chem.33 2264-2270；Jones,A.S.,McGuigan,C.,Walker,R.T.,Balzarini,J.and DeClercq,E.(1984)"Synthesis,properties,and biological activity of some nucleoside cyclicphosphoramidates."J.Chem.Soc.Perkin Trans.I,1471-1474；Juodka,B.A.and Smrt,J.(1974)"Synthesis of diribonucleoside phosph(P.fwdarw.N)amino acidderivatives."Coll.Czech.Chem.Comm.39,363-968；Kataoka,S.,Imai,J.,Yamaji,N.,Kato,M.,Saito,M.,Kawada,T.and Imai,S.(1989)"Alkylated cAMP derivatives；selective synthesis and biological activities."Nucleic Acids Res.Sym.Ser.21,1-2；Kataoka,S.,Uchida,"(cAMP)benzyl and methyl triesters."Heterocycles 32,1351-1356；Kinchington,D.,Harvey,J.J.,O'Connor,T.J.,Jones,B.C.N.M.,Devine,K.G.,Taylor-Robinson D.,Jeffries,D.J.and McGuigan,C.(1992)"Comparison ofantiviral effects of zidovudine phosphoramidate an dphosphorodiamidatederivates against HIV and ULV in vitro."Antiviral Chem.Chemother.3,107-112；Kodama,K.,Morozumi,M.,Saithoh,K.I.,Kuninaka,H.,Yosino,H.and Saneyoshi,M.(1989)"Antitumor activity and pharmacology of 1-.beta.-D-arabinofuranosylcytosine-5'-stearylphosphate；an orally active derivative of1-.beta.-D-arabinofuranosylcytosine."Jpn.J.Cancer Res.80,679-685；Korty,M.andEngels,J.(1979)"The effects of adenosine-and guanosine 3',5'phosphoric andacid benzyl esters on guinea-pig ventricular myocardium."Naunyn-Schmiedeberg's Arch.Pharmacol.310,103-111；Kumar,A.,Goe,P.L.,Jones,A.S.Walker,R.T.Balzarini,J.and DeClercq,E.(1990)"Synthesis and biological evaluation ofsome cyclic phosphoramidate nucleoside derivatives."J.Med.Chem,33,2368-2375；LeBec,C.,and Huynh-Dinh,T.(1991)"Synthesis of lipophilic phosphate triesterderivatives of 5-fluorouridine an arabinocytidine as anticancer prodrugs."Tetrahedron Lett.32,6553-6556；Lichtenstein,J.,Barner,H.D.and Cohen,S.S.(1960)"The metabolism of exogenously supplied nucleotides by Escherichiacoli.,"J.Biol.Chem.235,457-465；Lucthy,J.,Von Daeniken,A.,Friederich,J.Manthey,B.,Zweifel,J.,Schlatter,C.and Benn,M.H.(1981)"Synthesis andtoxicological properties of three naturally occurring cyanoepithioalkanes".Mitt.Geg.Lebensmittelunters.Hyg.72,131-133(Chem.Abstr.95,127093)；McGigan,C.Tollerfield,S.M.and Riley,P.a.(1989)"Synthesis and biological evaluation ofsome phosphate triester derivatives of the antiviral drug Ara."Nucleic AcidsRes.17,6065-6075；McGuigan,C.,Devine,K.G.,O'Connor,T.J.,Galpin,S.A.,Jeffries,D.J.and Kinchington,D.(1990a)"Synthesis and evaluation of some novelphosphoramidate derivatives of 3'-azido-3'-deoxythymidine(AZT)as anti-HIVcompounds."Antiviral Chem.Chemother.1 107-113；McGuigan,C.,O'Connor,T.J.,Nicholls,S.R.Nickson,C.and Kinchington,D.(1990b)"Synthesis and anti-HIVactivity of some novel substituted dialkyl phosphate derivatives of AZT andddCyd."Antiviral Chem.Chemother.1,355-360；McGuigan,C.,Nicholls,S.R.,O'Connor,T.J.,and Kinchington,D.(1990c)"Synthesis of some novel dialkyl phosphatederivative of 3'-modified nucleosides as potential anti-AIDS drugs."AntiviralChem.Chemother.1,25-33；McGuigan,C.,Devin,K.G.,O'Connor,T.J.,and Kinchington,D.(1991)"Synthesis and anti-HIV activity of some haloalkyl phosphoramidatederivatives of 3'-azido-3'-deoxythylmidine(AZT)；potent activity of thetrichloroethyl methoxyalaninyl compound."Antiviral Res.15,255-263；McGuigan,C.,Pathirana,R.N.,Balzarini,J.and DeClercq,E.(1993b)"Intracellular deliveryof bioactive AZT nucleotides by aryl phosphate derivatives of AZT."J.Med.Chem.36,1048-1052。
II.活性化合物
在一个实施方案中，所述化合物具有下式：
或其药学上可接受的盐或前药。
在该式中：
X和Z之一选自由以下组成的组：-NH-、-N(NH2)-、-NH(OH)-、N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-、-O-、-CH2-、-CH(C1-10烷基)-、C(C1-10烷基)2-、-CH(C3-10环烷基)-、-CH(C2-10烯基、-CH(C2-10炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O-C1-10烷基)-、-CH(NH2)-、-CH(NH-C1-10烷基)-和-CH(C(O)NH2)-，
而X和Z中的另一个选自由以下组成的组：-C(O)-、-SO2-、-N(C(O)-、-CH2-、-CH(C1-10烷基)-、C(C1-10烷基)2-、-CH(C3-10环烷基)-、-CH(C2-10烯基、-CH(C2-10炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O烷基)-、-CH(NH2)-、-CH(NHC1-10烷基)-和-CH(C(O)NH2)-，
Y选自以下组成的组：-NH、-N(NH2)-、-NH(OH)-、N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-、-O-、-CH2-、-CH(C1-10烷基)-、-CH(C3-10环烷基)-、-CH(C2-10烯基、-CH(C2-10炔基)-、-CH(芳基)-、-CH(杂芳基)-、-C(C1-10烷基)2-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O-C1-10烷基)-、-C(O)-、-SO2-、-N(C(O)-C1-10烷基)-、-N(C(O)O-C1-10烷基)-、-CH(NH2)-、-CH(NH-C1-10烷基)-和-CH(C(O)NH2)-，
A和B独立地是苯基、含有一个、两个或三个氮、氧或硫原子的五元杂芳族环或含有一个、两个或三个氮原子的六元杂芳族环；
u和v独立地为0、1、2、3或4；条件是u和v中的至少一个为1、2、3或4；
每个R1和R2独立地为R3、OH、OR3、SR3、S(O)R3、SO2R3、C(O)R3、C(O)OR3、OC(O)R3、OC(O)OR3、NH2、NHR3、NHC(O)R3、NR3C(O)R3、NHS(O)2R3、NR3S(O)2R3、NHC(O)OR3、NR3C(O)OR3、NHC(O)NH2、NHC(O)NHR3、NHC(O)N(R3)2、NR3C(O)N(R3)2、C(O)NH2、C(O)NHR3、C(O)N(R3)2、C(O)NHOH、C(O)NHOR3、C(O)NHSO2R3、C(O)NR3SO2R3、SO2NH2、SO2NHR3、SO2N(R3)2、COOH、C(O)H、C(N)NH2、C(N)NHR3、C(N)N(R3)2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、-CH2-膦酸酯、-CH2O-磷酸酯、CH2P(O)(OH)2、CH2P(O)(OR3)2、CH2P(O)(OR3)(NR3)、CH2P(O)(NR3)2、CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)或CH2-环Sal单磷酸酯前药，
其中术语磷酸酯包括单磷酸酯、二磷酸酯、三磷酸酯和稳定化的磷酸酯前药，术语膦酸酯包括与磷酸酯前药中存在的前药相同的前药，
并且当R1和R2在相邻的碳上时，它们可以一起形成饱和或不饱和的烷基、芳族或杂芳族环；
每个R3独立地为芳基、杂芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基或C2-10炔基，其中每一个未被取代或独立地被一个或多个选自以下组的取代基取代：R4、OH、OR4、SR4、S(O)R4、SO2R4、C(O)R4、C(O)OR4、OC(O)R4、OC(O)OR4、NH2、NHR4、NHC(O)R4、NR4C(O)R4、NHS(O)2R4、NR4S(O)2R4、NHC(O)OR4、NR4C(O)OR4、NHC(O)NH2、NHC(O)NHR4、NHC(O)N(R4)2、NR4C(O)N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2、C(O)NHOH、C(O)NHOR4、C(O)NHSO2R4、C(O)NR4SO2R4、SO2NH2、SO2NHR4、SO2N(R4)2、COOH、C(O)H、C(N)NH2、C(N)NHR4、C(N)N(R4)2、C(N)OH、C(N)OCH4、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)、cycloSal单磷酸酯前药、CH2P(O)(OH)2、CH2P(O)(OR4)2、CH2P(O)(OR4)(NR4)、CH2P(O)(NR4)2、CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)和CH2-环Sal单磷酸酯前药，
每个R4独立地选自芳基、杂芳基、芳基烷基、烷基芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基和C2-10炔基，其中每一个是未取代的或独立地被一个或多个选自以下组的取代基取代：R5、OH、OR5、SR5、S(O)R5、SO2R5、C(O)R5、C(O)OR5、OC(O)R5、OC(O)OR5、NH2、NHR5、NHC(O)R5、NR5C(O)R5、NHS(O)2R5、NR5S(O)2R5、NHC(O)OR5、NR5C(O)OR5、NHC(O)NH2、NHC(O)NHR5、NHC(O)N(R5)2、NR5C(O)N(R5)2、C(O)NH2、C(O)NHR5、C(O)N(R5)2、C(O)NHOH、C(O)NHOR5、C(O)NHSO2R5、C(O)NR5SO2R5、SO2NH2、SO2NHR5、SO2N(R5)2、COOH、C(O)H、C(N)NH2、C(N)NHR5、C(N)N(R5)2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)和环Sal单磷酸酯前药，
每个R5独立地为芳基、杂芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基或C2-10炔基，其中每一个是未取代的或独立地被一个或多个选自以下组的取代基取代：R6、OH、OR6、SR6、S(O)R6、SO2R6、C(O)R6、C(O)OR6、OC(O)R6、OC(O)OR6、NH2、NHR6、NHC(O)R6、NR6C(O)R6、NHS(O)2R6、NR6S(O)2R6、NHC(O)OR6、NR6C(O)OR6、NHC(O)NH2、NHC(O)NHR6、NHC(O)N(R6)2、NR6C(O)N(R6)2、C(O)NH2、C(O)NHR6、C(O)N(R6)2、C(O)NHOH、C(O)NHOR6、C(O)NHSO2R6、C(O)NR6SO2R6、SO2NH2、SO2NHR6、SO2N(R6)2、COOH、C(O)H、C(N)NH2、C(N)NHR6、C(N)N(R6)2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br、I、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)和环Sal单磷酸酯前药，
每个R6独立地为芳基、杂芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基或C2-10炔基，其中每一个是未取代的或独立地被一个或多个选自以下组的取代基取代：C1-10烷基、C2-10烯基、C2-10炔基、OH、NH2、C(O)NH2、C(O)NHOH、SO2NH2、COOH、C(O)H、C(N)NH2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)和环Sal单磷酸酯前药。
这些化合物的药学上可接受的盐和前药也旨在本发明的范围内。
代表性的R2结构部分如下所示：
代表性的R3结构部分如下所示：
在一个实施方案中，X和Z之一为-C(O)-、-SO2-或-NC(O)-，并且另一个为-NH-、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-或-O-。
在另一个实施方案中，X和Z之一为-C(O)-、-SO2-或-N(C(O)-，并且另一个为-CH2-、-CH(C1-6烷基)-、C(烷基)2-、-CH(C3-8环烷基)-、-CH(C2-6烯基、-CH(C2-6炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O烷基)-、-CH(NH2)-、-CH(NH烷基)-或-CH(C(O)NH2)-。4、根据权利要求1所述的化合物，其中X和Z之一为-NH-、-N(NH2)-、-NH(OH)-、-N(烷基)-或-O-，并且另一个为-CH2-、-CH(C1-6烷基)-、C(烷基)2-、-CH(C3-8环烷基)-、-CH(C2-6烯基、-CH(C2-6炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O烷基)-、-CH(NH2)-、-CH(NH烷基)-或-CH(C(O)NH2)-。
在第三个实施方案中，X和Z之一为-NH-、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-，并且另一个为-C(O)-或-SO2-。
在第四个实施方案中，Y为-NH、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-或-O-。
在第五个实施方案中，Y为-NH、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-，
在第六个实施方案中，R1和R2之一是H、-CH2-膦酸酯、-CH2O-磷酸酯，其中术语磷酸酯包括单磷酸酯、二磷酸酯、三磷酸酯和稳定化的磷酸酯前药，术语膦酸酯包括与磷酸酯前药中存在的前药相同的前药。
在第七个实施方案中，R1和R2之一为H、-CH2P(O)(OH)2、-CH2P(O)(OH)(OR6)、-CH2P(O)(OR6)2、-CH2P(O)(OR6)(NR6)、-CH2P(O)(NR6)2、-CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)或-CH2-环Sal单磷酸酯前药。
在该实施方案的一个方面，R1和R2之一是膦酸酯、氨基磷酸酯、环Sal单磷酸酯前药，或具有下式-CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)。
在一个实施方案中，R1和R2之一为-C(O)NHR4、-C(O)N(R4)2、
其中R4为C1-10烷基、C3-10环烷基、C2-10烯基、C2-10炔基、芳基烷基、烷基芳基、C1-10卤代烷基、C1-10烷基-芳基或C1-10卤代烷基-芳基，并且m为0、1或2。在特定的实施方案中，R4是C1-10烷基-芳基，并且苄基是特别优选的R4取代基。
在另一个实施例中，R1和R2之一为-C(O)-C1-10烷基、-C(O)-烷基芳基、-C(O)-杂环基-烷基芳基、-C(O)-杂环基-CH2-芳基、-C(O)-杂环基-CF2-芳基、-C(O)-环烷基-烷基芳基、-C(O)NHC1-10烷基、-C(O)NH-烷基芳基、-C(O)NH-杂环基-烷基芳基、-C(O)NH-杂环基-CF2-芳基、-C(O)NH-环烷基-烷基芳基、-SO2-C1-10烷基、-SO2-烷基芳基、-SO2-杂环基-烷基芳基、-SO2-杂环基-CF2-芳基或-SO2-环烷基-烷基芳基。
代表性的化合物包括以下：
或其药学上可接受的盐或前药。
特别优选的化合物具有下式：
或其药学上可接受的盐或前药。
III立体异构现象和多晶型现象
本文所述的化合物可具有不对称中心，可以以外消旋体、外消旋混合物、单独的非对映异构体或对映异构体存在，所有异构形式均包括在本发明中。具有手性中心的本发明化合物可以以光学活性和外消旋形式存在和分离。一些化合物可以表现出多晶型。本发明包括具有本文所述的有用性质的本发明化合物的外消旋、光学活性、多晶型或立体异构形式或其混合物。光学活性形式可以通过例如以下方式来制备：通过重结晶技术拆分外消旋形式、通过从光学活性起始材料合成、通过手性合成或通过使用手性固定相的色谱分离或通过酶促拆分。可以纯化相应的化合物，然后衍生该化合物以形成本文所述的化合物，或纯化化合物本身。
光学活性形式的化合物可以使用本领域已知的任意方法制备，包括但不限于通过重结晶技术拆分外消旋形式、通过从光学活性起始材料合成、通过手性合成或通过使用手性固定相的色谱分离。
获得光学活性材料的方法的实例包括至少下列方法：
i)晶体物理分离法：手动分离各个对映异构体的宏观晶体的技术。如果存在单独的对映异构体的晶体，即原料是团聚体(conglomerate)且所述晶体是视觉上可区分的，则可采用该技术；
ii)同时结晶法：从外消旋体的溶液中分别结晶出各个对映异构体的技术，可能只有当外消旋体是固态的团聚体时才可行；
iii)酶促拆分法：借助对映异构体与酶反应的不同速率，部分或完全分离外消旋体的技术；
iv)酶促不对称合成法：至少一个合成步骤采用酶促反应以获得所需对映异构体的对映异构体纯的或富集的合成前体的合成技术；
v)化学不对称合成法：在产物中产生不对称(即手性)的条件下从非手性前体合成所需对映异构体的合成技术，其可使用手性催化剂或手性助剂来完成；
vi)非对映异构体分离法：使外消旋化合物与对映异构体纯试剂(手性助剂)反应，将各个对映异构体转化为非对映异构体的技术。然后所得非对映异构体借助其现在更明显的结构差异，通过色谱法或结晶法分离，随后除去手性助剂，获得所需的对映异构体；
vii)一级和二级不对称转化法：该技术通过平衡来自外消旋体的非对映异构体，使其在来自所需对映异构体的非对映异构体的溶液中占优势，或者来自所需对映异构体的非对映异构体的优先结晶作用破坏了这种平衡，致使所有材料最终几乎都被转化为来自所需对映异构体的结晶型非对映异构体。然后从所述非对映异构体中释放出所需对映异构体；
viii)动力学拆分法：该技术是指借助对映异构体与手性、非消旋试剂或催化剂在动力学条件下的不同反应速率，实现对外消旋体的部分或完全拆分(或者对部分拆分的化合物进一步拆分)；
ix)从非外消旋前体进行对映异构体专一性合成：从非手性原料获得所需对映异构体且在合成过程中没有或仅最小量地破坏立体化学完整性的合成技术；
x)手性液相色谱法：借助于外消旋体的对映异构体与固定相的相互作用不同而在液体流动相中分离出外消旋体的对映异构体的技术(包括但不限于通过手性HPLC)。所述固定相可由手性材料制得，或者所述流动相可包含引起不同相互作用的另外的手性材料；
xi)手性气相色谱法：通过使外消旋体挥发，并借助于对映异构体在气态流动相中与含有固定的非外消旋手性吸附相的柱子的不同相互作用而分离出对映异构体的技术；
xii)用手性溶剂萃取：借助一种对映异构体优先溶解于特定手性溶剂中而分离出对映异构体的技术；
xiii)跨手性膜转运法：使外消旋体与薄膜屏障接触的技术。该屏障通常分离出两种可混溶液体，其中一种含有外消旋体，驱动力如浓度差或压力差导致优先跨膜屏障转运。该膜的非外消旋手性性质仅允许外消旋体中的一种对映异构体通过，从而实现了分离。
在一个实施方案中使用手性色谱法，包括但不限于模拟移动床色谱法。各种手性固定相可商购获得。
IV.盐或前药制剂
在化合物具有足够的碱性或酸性以形成稳定的无毒酸盐或碱盐的情况下，将化合物作为药学上可接受的盐施用可能是合适的。药学上可接受的盐的实例是与酸形成的有机酸加成盐，其形成生理学上可接受的阴离子，例如甲苯磺酸盐、甲磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐和α-甘油磷酸盐。还可以形成合适的无机盐，包括但不限于硫酸盐、硝酸盐、碳酸氢盐和碳酸盐。对于某些透皮应用，可优选使用本文所述化合物的脂肪酸盐。脂肪酸盐可以帮助渗透角质层。合适的盐的实例包括化合物与硬脂酸、油酸、亚油酸、棕榈酸、辛酸和癸酸的盐。
药学上可接受的盐可以使用本领域熟知的标准方法获得，例如通过使足够碱性的化合物如胺与合适的酸(提供生理学上可接受的阴离子)反应。在化合物包括多个胺基的那些情况下，可以与任意数量的胺基形成盐。还可以制备羧酸的碱金属(例如钠、钾或锂)盐或碱土金属(例如钙)盐。
前药是一种药理学物质，其以无活性(或显著较低的活性)形式施用，并随后在体内代谢为活性代谢物。以较低剂量使更多药物到达所需靶标通常是使用前药背后的基本原理并且这通常归因于更好的吸收、分布、代谢和/或排泄(ADME)性质。前药通常设计成用于改善口服生物利用度，因为胃肠道吸收不良通常是限制因素。另外，使用前药策略可以增加药物对其预期靶标的选择性，从而降低脱靶效应的可能性。
V.治疗方法
可以通过向患者施用在药学上可接受的载体或稀释剂的存在下的有效量的活性化合物或其药学上可接受的前药或盐来治疗宿主。活性物质可以通过任意合适的途径施用，例如以液体或固体形式口服、胃肠外、静脉内、皮内、透皮、皮下或局部施用。在药物组合物中提供了施用的细节。
VI.组合或交替疗法
在一个实施方案中，式(A)的化合物或其药学上可接受的衍生物可以单独使用，与一种或多种式(A)的化合物或其药学上可接受的衍生物结合使用，或与至少一种其他剂结合使用，用于治疗与ROR相关的疾病。
在某些实施方案中，式(A)化合物用于治疗代谢紊乱，与抗糖尿病或抗胰岛素抵抗药剂例如但不限于格列酮、磺酰脲、二甲双胍、胰岛素、胰岛素模拟物、DPP4抑制剂、GLP1受体激动剂、胰高血糖素受体拮抗剂或抗肥胖剂结合使用。
在某些实施方案中，式(A)化合物用于治疗免疫疾病，与例如但不限于抗TNF剂或免疫抑制性糖皮质激素结合使用。在某些实施方案中，式(A)化合物用于治疗癌症，与一种或多种抗癌剂例如但不限于铂化合物、长春花生物碱或其类似物、紫杉烷、氮芥等结合使用。
联合使用的用于ROR相关病况的其他药物包括但不限于以下：胆固醇生物合成抑制剂(HMG CoA还原酶抑制剂，例如洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、西立伐他汀、尼伐他汀和利伐他汀)；角鲨烯环氧酶抑制剂(例如特比萘芬)；血浆HDL升高剂(例如CETP抑制剂，例如anacetrapib、R1658)；人过氧化物酶体增殖物激活受体(PPAR)γ激动剂(例如噻唑烷二酮，例如罗格列酮、曲格列酮和吡格列酮)；PPARα激动剂(例如，氯贝丁酯(clofibrate)、非诺贝特和吉非贝尼)；PPAR双α/γ激动剂(例如莫格列扎(muraglitazar)、阿格列扎(aleglitazar)、培格列扎(peliglitazar)、elafibranor)；法呢类X受体(FXR)调节剂(例如奥贝胆酸(obeticholic acid)、LMB763、LJN45等)；胆汁酸螯合剂(例如，阴离子交换树脂或季胺(例如，消胆胺或考来替泊(colestipol)))；胆汁酸转运抑制剂(BATi)；烟酸、烟酰胺；胆固醇吸收抑制剂(例如依折麦布(ezetimibe))；酰基辅酶A:胆固醇O-酰基转移酶(ACAT)抑制剂(例如阿伐麦布(avasimibe))；选择性雌激素受体调节剂(例如雷洛昔芬或他莫昔芬)；LXRα或β激动剂、拮抗剂或部分激动剂(例如22(R)-羟基胆固醇、24(S)-羟基胆固醇、T0901317或GW3965)；微粒体甘油三酸酯转移蛋白(MTP)抑制剂、抗糖尿病药例如胰岛素和胰岛素类似物(例如LysPro胰岛素、包含胰岛素的吸入制剂；磺酰脲类和类似物(例如甲苯磺酰胺、氯丙酰胺、格列吡嗪(glipizide)、格列美脲、格列本脲(glyburide)、格列本脲(glibenclamide)、甲苯磺丁脲、醋磺环已脲、格列吡嗪(glypizide))、双胍(例如二甲双胍或二甲双胍盐酸盐、苯乙双胍、丁双胍)α2拮抗剂和咪唑啉(例如咪格列唑(midaglizole)、伊格列醇(isaglidole)、德格列哚(deriglidole)、咪唑克生(idazoxan)、依法克生(efaroxan)、氟洛克生(fluparoxan))、噻唑烷二酮(例如吡格列酮盐酸盐、罗格列酮马来酸酯、西格列酮、曲格列酮或巴格列酮)、α-葡萄糖苷酶抑制剂(例如米格列醇、阿卡波糖、依帕司他或伏格列波糖)、美格列奈(例如瑞格列奈或那格列奈)、DPP-4抑制剂(例如磷酸西他列汀、沙格列汀、维达列汀、阿格列汀或地格列汀(denagliptin))、肠降血糖素(例如胰高血糖素样肽-1(GLP-1)受体激动剂(例如艾塞那肽)(ByettaTM)、NN2211(利拉鲁肽)、GLP-1(7-36)酰胺及其类似物、GLP-1(7-37)及其类似物、AVE-0010(ZP-10)、R1583(他司鲁泰(Taspoglutide))、GSK-716155(阿比鲁泰，GSK/人类基因组科学)、BRX-0585(辉瑞/Biorexis)和CJC-1134-PC(Exendin-4:PC-DACTM和葡萄糖依赖性促胰岛素肽(GIP))；胰岛淀粉样多肽激动剂(例如普兰林肽、AC-137)；胰岛素促泌剂(例如利诺格列(linogliride)、那格列奈、瑞格列奈、米格列奈钙水合物(mitiglinidecalcium hydrate)或美格列奈)；SGLT-2抑制剂(例如达格列净(BMS)、舍格列净(Kissei)、AVE 2268(Sanofi-Aventis)；葡糖激酶激活剂，例如WO 00/58293A1中公开的化合物；抗肥胖药，例如神经生长因子激动剂(例如，阿索开(axokine))、生长激素激动剂(例如AOD-9604)、肾上腺素摄取抑制剂(例如GW-320659)、5-HT(5-羟色胺)再摄取/转运抑制剂(例如Prozac)、5-HT/NA(5-羟色胺/去甲肾上腺素)再摄取抑制剂(例如西布曲明)、DA(多巴胺)再摄取抑制剂(例如安非他酮)、5-HT、NA和DA再摄取阻滞剂、甾体植物提取物(例如P57)、NPY1或5(神经肽Y Y1或Y5)拮抗剂、NPY2(神经肽Y Y2)激动剂、MC4(黑皮质素4)激动剂、CCK-A(胆囊收缩素A)激动剂、GHSR1a(生长激素促分泌素受体)拮抗剂/反向激动剂、生长素释放肽抗体、MCH1R(黑色素浓缩激素1R)拮抗剂(例如SNAP 7941)、MCH2R(黑色素浓缩激素2R)激动剂/拮抗剂、H3(组胺受体3)反向激动剂或拮抗剂、H1(组胺1受体)激动剂、FAS(脂肪酸合酶)抑制剂、ACC-1(乙酰辅酶A羧化酶-1)抑制剂、β3(β肾上腺素能受体3)激动剂、DGAT-2(二酰甘油酰基转移酶2)抑制剂、DGAT-1(二甘油甘油酰基转移酶1)抑制剂、CRF(促肾上腺皮质激素释放因子)激动剂、甘丙肽拮抗剂、UCP-1(解偶联蛋白-1)、2或3种激活剂、瘦蛋白或瘦蛋白衍生物、阿片样物质拮抗剂、食欲素拮抗剂、BRS3激动剂，GLP-1(胰高血糖素样肽1)激动剂、IL-6激动剂、α-MSH激动剂、AgRP拮抗剂、BRS3(bombesin受体亚型3)激动剂、5-HT1B激动剂、POMC拮抗剂、CNTF(纤毛神经营养因子或CNTF衍生物)、NN2211、托吡酯、糖皮质激素拮抗剂、Exendin-4激动剂、5-HT2C(5-羟色胺受体2C)激动剂(例如氯卡色林(Lorcaserin))、PDE(磷酸二酯酶)抑制剂、脂肪酸转运蛋白抑制剂、二羧酸酯转运蛋白抑制剂、葡萄糖转运蛋白抑制剂、CB-1(大麻素1受体)反向激动剂或拮抗剂(例如SR141716)、脂肪酶抑制剂(例如奥利司他)；环氧合酶2(COX-2)抑制剂(例如罗非考昔和塞来昔布)；凝血酶抑制剂(例如肝素、阿加曲班、美拉加群、达比加群)；血小板凝集抑制剂(例如糖蛋白IIb/IIIa纤维蛋白原受体拮抗剂或阿司匹林)；维生素B6及其药学上可接受的盐；维生素B12；维生素E；叶酸或其药学上可接受的盐或酯；抗氧化剂维生素，例如C、E和β-胡萝卜素；β受体阻滞剂(例如血管紧张素II受体拮抗剂，如氯沙坦、厄贝沙坦或缬沙坦；抗降压素转化酶抑制剂，例如依那普利和卡托普利；钙通道阻滞剂，例如硝苯地平和地尔硫卓；内皮拮抗剂；阿司匹林；脂肪酸/胆汁酸结合物(芳族胆固醇)；半胱天冬酶抑制剂(emricasan)；免疫调节剂(Cenicriviroc等)；甲状腺激素受体调节剂(MB07811、MGL-3196等)；除LXR配体以外的可增强ATP结合盒式转运蛋白Al基因表达的剂；以及双膦酸盐化合物(例如阿仑膦酸钠)。
在某些实施方案中，式(A)的化合物与至少一种其他修饰宿主代谢的剂组合，例如但不限于克拉霉素、可比司他(cobicistat)、茚地那韦、伊曲康唑、酮康唑、奈法唑酮、利托那韦、沙奎那韦、舒倍生(suboxone)、泰利霉素(telithromycin)、阿瑞匹坦、红霉素、氟康唑、维拉帕米、地尔硫卓、西咪替丁、胺碘酮、博普瑞韦(boceprevir)、氯霉素、环丙沙星、地拉韦啶、二乙基-二硫代氨基甲酸酯、氟伏沙明、孕二烯酮、伊马替尼、米贝地尔、米非司酮、诺氟沙星、诺氟西汀、特拉普韦和伏立康唑。
可共同施用的其他化合物包括谷胱甘肽、二和三甲基甘氨酸、胆碱、乙酰胆碱、烟酸、镁、维生素D、cucurmin、小檗碱、辅酶Q10和sylmarin(乳蓟)中的一种或多种。
VIII.药物组合物
受肝脏或代谢性疾病影响的宿主(包括但不限于人类)例如但不限于血脂和胆固醇水平升高，尤其是高LDL-胆固醇、高甘油三酸酯、低HDL-胆固醇、血脂异常、胆固醇吸收疾病、动脉粥样硬化疾病、冠状动脉疾病、脑血管动脉疾病、外周血管疾病、主动脉瘤、颈动脉粥样硬化疾病、胆汁淤积性疾病、外周闭塞性疾病、缺血性中风、糖尿病尤其是非胰岛素依赖型糖尿病、代谢综合征、糖尿病性肾病、肥胖症(其中肥胖症的治疗可能导致体重减轻)、胆固醇胆结石病、肝的胆汁淤积/纤维化、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、肝缺血再灌注损伤或非酒精性脂肪肝疾病(NAFLD)；自身免疫性疾病，例如但不限于类风湿性关节炎、强直性脊柱炎、红斑狼疮、牛皮癣、银屑病关节炎、特应性湿疹、炎症性肠病例如克罗恩病、哮喘、粘膜利什曼病、多发性硬化症、系统性硬化、1型糖尿病、川崎病、桥本氏甲状腺炎(Hashimoto'sthyroiditis)、恶性贫血、慢性移植物抗宿主病、急性移植物抗宿主病、乳糜泻、特发性血小板减少性血栓性紫癜、重症肌无力、干燥综合征(Sjorgren's syndrome)、硬皮病、溃疡性结肠炎、溃疡性结肠炎、表皮增生、肾小球肾炎、慢性阻塞性肺疾病(COPD)和肌萎缩性侧索硬化；或与ROR相关的中枢神经系统(CNS)疾病，例如但不限于睡眠障碍、焦虑症或神经退行性疾病例如帕金森氏症或阿尔茨海默氏病；或者可以通过向患者施用在药学上可接受的载体或稀释剂的存在下的有效量的活性化合物或其药学上可接受的前药或盐来治疗的癌症，例如但不限于结肠癌、前列腺癌、乳腺癌、淋巴样癌、脑癌、髓样癌等。活性物质可以通过任意合适的途径施用，例如以液体或固体形式口服、胃肠外、静脉内、皮内、皮下或局部施用。
优选的化合物剂量范围为每天约0.01至约10mg/kg，更通常为约0.1至5mg/kg，优选约0.5至约2mg/kg接收者的体重。药学上可接受的盐和前药的有效剂量范围可以基于待递送的母体化合物的重量来计算。如果盐或前药本身表现出活性，则可以使用盐或前药的重量如上估算有效剂量，或通过本领域技术人员已知的其他方法估算有效剂量。
化合物可方便地以任意合适的剂型单位施用，包括但不限于每单位剂型含有7至600mg，优选70至600mg活性成分的剂型。5-400mg的口服剂量通常是方便的。
药物组合物中活性化合物的浓度将取决于药物的吸收、失活和排泄速率以及本领域技术人员已知的其他因素。应注意，剂量值也将随待缓解的病况的严重程度而变化。还应理解的是，对于任意特定受试者，应根据个体需要和施用或监督组合物施用的人的专业判断随时间调整具体的剂量方案，并且本文所述的浓度范围仅是示例性的，并非旨在限制要求保护的组合物的范围或实践。活性成分可以一次施用，或者可以分成许多较小的剂量，以不同的时间间隔施用。
活性化合物的优选施用方式是口服。口服组合物通常包括惰性稀释剂或可食用载体。可以将它们封装在明胶胶囊中或压制成片剂。为了治疗性口服施用的目的，可以将活性化合物与赋形剂合并，并以片剂、锭剂或胶囊的形式使用。可以包含药学上相容的粘合剂和/或佐剂材料作为组合物的一部分。
片剂、丸剂、胶囊剂、锭剂等可以含有任意下列成分或类似性质的化合物：粘合剂如微晶纤维素、黄蓍胶或明胶；赋形剂如淀粉或乳糖，崩解剂如海藻酸、Primogel或玉米淀粉；润滑剂如硬脂酸镁或Sterotes；助流剂如胶体二氧化硅；甜味剂如蔗糖或糖精；或调味剂如薄荷、水杨酸甲酯或橙味调味剂。当剂量单位形式是胶囊时，除了上述类型的材料外，它还可以含有液体载体如脂肪油。另外，单位剂型可含有改变剂量单位的物理形式的各种其他物质，例如糖、虫胶或其他肠溶剂的包衣。
化合物可以作为酏剂、悬浮液、糖浆、薄片剂(wafer)、口香糖等的组分施用。除活性化合物外，糖浆还可含有作为甜味剂的蔗糖和某些防腐剂、染料和着色剂和调味剂。
化合物或其药学上可接受的前药或盐也可以与不损害所需作用的其它活性物质混合，或与补充所需作用的物质混合，例如抗生素、抗真菌剂、抗炎剂或其它抗病毒化合物。用于肠胃外、皮内、皮下或局部施用的溶液或悬浮液可包括以下组分：无菌稀释剂如注射用水、盐溶液、固定油、聚乙二醇、甘油、丙二醇或其他合成溶剂；抗菌剂如苯甲醇或对羟基苯甲酸甲酯；抗氧化剂如抗坏血酸或亚硫酸氢钠；螯合剂，如乙二胺四乙酸；缓冲剂，如乙酸盐、柠檬酸盐或磷酸盐，以及调节张力的剂，如氯化钠或右旋糖。可以将肠胃外制剂封装在安瓿、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。
如果静脉内施用，则优选的载体是生理盐水或磷酸盐缓冲盐水(PBS)。
透皮制剂
在一些实施方案中，组合物以透皮制剂的形式存在，例如在FDA批准的激动剂罗替戈汀(rotigitine)透皮贴剂(Neupro贴剂)中使用的制剂。另一种合适的制剂描述于题为“Transdermal Therapeutic System for Treating Parkinsonism”的美国公开号20080050424中。该制剂包括基于硅氧烷或丙烯酸酯的粘合剂，并且可包括增加活性物质的溶解度的添加剂，其量能有效增加基质对活性物质的溶解能力。
透皮制剂可以是单相基质(matrices)，其包括背衬层、含活性物质的自粘基质和在使用前要除去的保护膜。更复杂的实施方案包括还可以含有非粘性层和控制膜的多层基质。如果使用聚丙烯酸酯粘合剂，它可以与多价金属离子如锌、钙、铝或钛离子交联，例如乙酰丙酮铝和乙酰丙酮钛。
当使用有机硅粘合剂时，它们通常是聚二甲基硅氧烷。然而，原则上可能存在其他有机残基，例如乙基或苯基，而不是甲基。因为活性化合物是胺，所以使用耐胺粘合剂可能是有利的。代表性的耐胺粘合剂描述于例如EP 0 180 377中。
代表性的基于丙烯酸酯的聚合物粘合剂包括丙烯酸、丙烯酰胺、丙烯酸己酯、丙烯酸2-乙基己酯、丙烯酸羟乙酯、丙烯酸辛酯、丙烯酸丁酯、丙烯酸甲酯、丙烯酸缩水甘油酯、甲基丙烯酸、甲基丙烯酰胺、甲基丙烯酸己酯、甲基丙烯酸2-乙基己酯、甲基丙烯酸辛酯、甲基丙烯酸甲酯、甲基丙烯酸缩水甘油酯、乙酸乙烯酯、乙烯基吡咯烷酮及其组合。
粘合剂必须具有适合于活性物质的溶解能力，并且活性物质必须能够在基质内移动，并且能够穿过接触表面到达皮肤。本领域技术人员可以容易地配制具有活性物质的适当透皮转运的透皮制剂。
某些药学上可接受的盐倾向于更优选用于透皮制剂，因为它们可以帮助活性物质通过角质层的屏障。实例包括脂肪酸盐，例如硬脂酸盐和油酸盐。油酸盐和硬脂酸盐是相对亲脂性的，甚至可以作为皮肤中的渗透增强剂。
也可以使用渗透增强剂。代表性的渗透增强剂包括脂肪醇、脂肪酸、脂肪酸酯、脂肪酸酰胺、甘油或其脂肪酸酯、N-甲基吡咯烷酮、萜烯如柠檬烯、α-蒎烯(pinene)、α-萜品醇、香芹酮、香芹醇、柠檬烯氧化物、蒎烯氧化物和1,8-桉叶油素。
贴剂通常可以通过将活性剂溶解或悬浮在乙醇或另一种合适的有机溶剂中，然后在搅拌下加入粘合剂溶液来制备。可以向粘合剂溶液、活性物质溶液或含活性物质的粘合剂溶液中添加另外的辅助物质。然后可以将溶液涂覆到合适的片材上，除去溶剂，将背衬层层压到基质层上，并从整个层压材料中冲出贴剂。
纳米颗粒组合物
本文所述的化合物还可以以纳米颗粒组合物的形式施用。在一个实施方案中，控释纳米颗粒制剂包含待施用的纳米颗粒活性剂和使药剂在施用后的释放延长的速率控制聚合物。在该实施方案中，组合物可在施用后释放活性剂持续约2至约24小时或多达30天或更长的时间。包含纳米颗粒形式的活性剂的代表性控释制剂描述于例如美国专利号8,293,277中。
纳米颗粒组合物可以包含本文所述活性剂的颗粒，其具有吸附在其表面上或与其表面结合的非交联表面稳定剂。
纳米颗粒的平均粒度通常小于约800nm，更通常小于约600nm，更通常小于约400nm，小于约300nm，小于约250nm，小于约100nm，或小于约50nm。在该实施方案的一个方面，当通过光散射技术测量时，至少50％的活性剂颗粒的平均粒度分别小于约800、600、400、300、250、100或50nm。
多种表面稳定剂通常与纳米颗粒组合物一起使用，以防止颗粒结块或聚集。
代表性的表面稳定剂选自由以下组成的组：明胶、卵磷脂、葡聚糖、阿拉伯树胶、胆固醇、黄蓍胶、硬脂酸、苯扎氯铵、硬脂酸钙、单硬脂酸甘油酯、十八十六醇、聚西托醇(cetomacrogol)乳化蜡、脱水山梨醇酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨糖醇脂肪酸酯、聚乙二醇、聚氧乙烯硬脂酸酯、胶体二氧化硅、磷酸酯、十二烷基硫酸钠、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非结晶纤维素、硅酸铝镁、三乙醇胺、聚乙烯醇、聚乙烯吡咯烷酮、泰洛沙泊(tyloxapol)、泊洛沙姆(poloxamer)、泊洛沙胺(poloxamine)、泊洛沙胺908、磺基琥珀酸钠二烷基酯、月桂基硫酸钠、烷基芳基聚醚磺酸酯、蔗糖硬脂酸酯和蔗糖二硬脂酸酯的混合物、对异壬基苯氧基聚-(缩水甘油)、SA9OHCO、癸酰基-N-甲基葡糖酰胺、正癸基-D-吡喃葡萄糖苷、正癸基-D-吡喃麦芽糖苷、正十二烷基-D-吡喃葡萄糖苷、正十二烷基-D-麦芽糖苷、庚酰基-N-甲基葡糖酰胺、正庚基-D-吡喃葡萄糖苷、正庚基-D-硫代葡萄糖苷、正己基-D-吡喃葡糖苷、壬酰基-N-甲基葡糖酰胺、正壬基-D-吡喃葡萄糖苷、辛酰基-N-甲基葡糖酰胺、正辛基-D-吡喃葡萄糖苷和辛基-D-硫代吡喃葡萄糖苷。溶菌酶也可用作纳米颗粒组合物的表面稳定剂。已知某些纳米颗粒如聚(乳酸-共-乙醇酸)(PLGA)-纳米颗粒在通过静脉内(IV)或皮下(SQ)给药时靶向肝脏。
可以将纳米颗粒配制到其中的代表性速率控制聚合物包括壳聚糖、聚环氧乙烷(PEO)、聚乙酸乙烯邻苯二甲酸酯、阿拉伯树胶、琼脂、瓜尔胶、谷物胶、葡聚糖、酪蛋白、明胶、果胶、角叉菜胶、蜡、虫胶、氢化植物油、聚乙烯吡咯烷酮、羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(CMC)、聚(乙烯)氧化物、烷基纤维素、乙基纤维素、甲基纤维素、羧甲基纤维素、亲水性纤维素衍生物、聚乙二醇、聚乙烯吡咯烷酮、乙酸纤维素、乙酸丁酸纤维素、乙酸邻苯二甲酸纤维素、乙酸偏苯三酸纤维素、聚乙酸乙烯邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、乙酸羟丙基甲基纤维素琥珀酸酯、聚乙烯醇缩乙醛二乙氨基乙酸酯、聚(甲基丙烯酸烷基酯)、聚(乙酸乙烯酯)、衍生自丙烯酸或甲基丙烯酸及其各自的酯的聚合物和衍生自丙烯酸或甲基丙烯酸及其各自的酯的共聚物。
制备纳米颗粒组合物的方法描述于例如美国专利号5,518,187和5,862,999，均关于“Method of Grinding Pharmaceutical Substances”；美国专利号5,718,388，关于“Continuous Method of Grinding Pharmaceutical Substances”；和美国专利号5,510,118关于“Process of Preparing Therapeutic Compositions ContainingNanoparticles”。
纳米颗粒组合物还描述于例如美国专利号5,298,262关于“Use of Ionic CloudPoint Modifiers to Prevent Particle Aggregation During Sterilization”；美国专利号5,302,401关于“Method to Reduce Particle Size Growth DuringLyophilization”；美国专利号5,318,767关于“X-Ray Contrast Compositions Useful inMedical Imaging”；美国专利号5,326,552关于“Novel Formulation ForNanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular WeightNon-ionic Surfactants”；美国专利号5,328,404关于“Method of X-Ray Imaging UsingIodinated Aromatic Propanedioates”；美国专利号5,336,507关于“Use of ChargedPhospholipids to Reduce Nanoparticle Aggregation”；美国专利号5,340,564forFormulations Comprising Olin 10-G to Prevent Particle Aggregation andIncrease Stability”；美国专利号5,346,702关于“Use of Non-Ionic Cloud PointModifiers to Minimize Nanoparticulate Aggregation During Sterilization”；美国专利号5,349,957关于“Preparation and Magnetic Properties of Very SmallMagnetic-Dextran Particles”；美国专利号5,352,459关于“Use of Purified SurfaceModifiers to Prevent Particle Aggregation During Sterilization”；美国专利号5,399,363和5,494,683，均关于“Surface Modified Anticancer Nanoparticles”；美国专利号5,401,492关于“Water Insoluble Non-Magnetic Manganese Particles as MagneticResonance Enhancement Agents”；美国专利号5,429,824关于“Use of Tyloxapol as aNanoparticulate Stabilizer”；美国专利号5,447,710关于“Method for MakingNanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular WeightNon-ionic Surfactants”；美国专利号5,451,393关于“X-Ray Contrast CompositionsUseful in Medical Imaging”；美国专利号5,466,440关于“Formulations of OralGastrointestinal Diagnostic X-Ray Contrast Agents in Combination withPharmaceutically Acceptable Clays”；美国专利号5,470,583关于“Method ofPreparing Nanoparticle Compositions Containing Charged Phospholipids toReduce Aggregation”；美国专利号5,472,683关于“Nanoparticulate Diagnostic MixedCarbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and LymphaticSystem Imaging”；美国专利号5,500,204关于“Nanoparticulate Diagnostic Dimers asX-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging”；美国专利号5,518,738关于“Nanoparticulate NSAID Formulations”；美国专利号5,521,218关于“Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents”；美国专利号5,525,328关于“Nanoparticulate Diagnostic Diatrizoxy Ester X-RayContrast Agents for Blood Pool and Lymphatic System Imaging”；美国专利号5,543,133关于“Process of Preparing X-Ray Contrast Compositions ContainingNanoparticles”；美国专利号5,552,160关于“Surface Modified NSAID Nanoparticles”；美国专利号5,560,931关于“Formulations of Compounds as NanoparticulateDispersions in Digestible Oils or Fatty Acids”；美国专利号5,565,188关于“Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles”；美国专利号5,569,448关于“Sulfated Non-ionic Block Copolymer Surfactant as StabilizerCoatings for Nanoparticle Compositions”；美国专利号5,571,536关于“Formulationsof Compounds as Nanoparticulate Dispersions in Digestible Oils or FattyAcids”；美国专利号5,573,749关于“Nanoparticulate Diagnostic Mixed CarboxylicAnhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic SystemImaging”；美国专利号5,573,750关于“Diagnostic Imaging X-Ray Contrast Agents”；美国专利号5,573,783关于“Redispersible Nanoparticulate Film Matrices WithProtective Overcoats”；美国专利号5,580,579关于“Site-specific Adhesion Withinthe GI Tract Using Nanoparticles Stabilized by High Molecular Weight,LinearPoly(ethylene Oxide)Polymers”；美国专利号5,585,108关于“Formulations of OralGastrointestinal Therapeutic Agents in Combination with PharmaceuticallyAcceptable Clays”；美国专利号5,587,143关于“Butylene Oxide-Ethylene Oxide BlockCopolymers Surfactants as Stabilizer Coatings for NanoparticulateCompositions”；美国专利号5,591,456关于“Milled Naproxen with HydroxypropylCellulose as Dispersion Stabilizer”；美国专利号5,593,657关于“Novel Barium SaltFormulations Stabilized by Non-ionic and Anionic Stabilizers”；美国专利号5,622,938关于“Sugar Based Surfactant for Nanocrystals”；美国专利号5,628,981关于“Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray ContrastAgents and Oral Gastrointestinal Therapeutic Agents”；美国专利号5,643,552关于“Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray ContrastAgents for Blood Pool and Lymphatic System Imaging”；美国专利号5,718,388关于“Continuous Method of Grinding Pharmaceutical Substances”；美国专利号5,718,919关于“Nanoparticles Containing the R(-)Enantiomer of Ibuprofen”；美国专利号5,747,001关于“Aerosols Containing Beclomethasone Nanoparticle Dispersions”；美国专利号5,834,025关于“Reduction of Intravenously Administered NanoparticulateFormulation Induced Adverse Physiological Reactions”；美国专利号6,045,829“Nanocrystalline Formulations of Human Immunodeficiency Virus(HIV)ProteaseInhibitors Using Cellulosic Surface Stabilizers”；美国专利号6,068,858关于“Methods of Making Nanocrystalline Formulations of Human ImmunodeficiencyVirus(HIV)Protease Inhibitors Using Cellulosic Surface Stabilizers”；美国专利号6,153,225关于“Injectable Formulations of Nanoparticulate Naproxen”；美国专利号6,165,506关于“New Solid Dose Form of Nanoparticulate Naproxen”；美国专利号6,221,400关于“Methods of Treating Mammals Using Nanocrystalline Formulations ofHuman Immunodeficiency Virus(HIV)Protease Inhibitors”；美国专利号6,264,922关于“Nebulized Aerosols Containing Nanoparticle Dispersions”；美国专利号6,267,989关于“Methods for Preventing Crystal Growth and Particle Aggregation inNanoparticle Compositions”；美国专利号6,270,806关于“Use of PEG-DerivatizedLipids as Surface Stabilizers for Nanoparticulate Compositions”；美国专利号6,316,029关于“Rapidly Disintegrating Solid Oral Dosage Form”，美国专利号6,375,986关于“Solid Dose Nanoparticulate Compositions Comprising a SynergisticCombination of a Polymeric Surface Stabilizer and Dioctyl SodiumSulfosuccinate”；美国专利号6,428,814关于“Bioadhesive nanoparticulatecompositions having cationic surface stabilizers”；美国专利号6,431,478关于“Small Scale Mill”；和美国专利号6,432,381关于“Methods for targeting drugdelivery to the upper and/or lower gastrointestinal tract”，所有这些都通过引用具体并入。此外，于2002年1月31日公开的美国专利申请号20020012675A1，关于“Controlled Release Nanoparticulate Compositions”，描述了纳米颗粒组合物，并且其通过引用具体并入。
无定形小颗粒组合物描述于例如美国专利号4,783,484关于“ParticulateComposition and Use Thereof as Antimicrobial Agent”；美国专利号4,826,689关于“Method for Making Uniformly Sized Particles from Water-Insoluble OrganicCompounds”；美国专利号4,997,454关于“Method for Making Uniformly-SizedParticles From Insoluble Compounds”；美国专利号5,741,522关于“Ultrasmall,Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Withinand Methods”；和美国专利号5,776,496，关于“Ultrasmall Porous Particles forEnhancing Ultrasound Back Scatter”。
某些纳米制剂可以通过以受控方式将药物释放到肠腔(lumen)中来增强药物的吸收，从而减少溶解性问题。肠壁旨在吸收营养物并充当病原体和大分子的屏障。小的两亲性和亲脂性分子可以通过分配到脂质双层中并通过被动扩散穿过肠上皮细胞而被吸收，而由于肠壁的内在性质，纳米制剂的吸收可能更复杂。纳米颗粒口服吸收的第一个物理障碍是覆盖肠和结肠腔表面的粘液屏障。粘液屏障包含不同的层，主要由被称为粘蛋白的高度糖基化的蛋白质组成，这些蛋白质可能会阻止某些纳米制剂的吸收。可以进行修饰以得到粘液渗透性增加的纳米制剂(Ensign等人，“Mucus penetrating nanoparticles:biophysical tool and method of drug and gene delivery,”Adv Mater 24:3887–3894(2012))。
穿过粘液层后，可以通过几个步骤来调节纳米制剂跨肠道上皮细胞的运输，包括细胞表面结合、内吞作用、细胞内运输和胞吐作用，从而实现可能涉及多个亚细胞结构的转胞吞作用(transcytosis)(跨细胞内部运输)。此外，纳米制剂还可以通过开放的紧密连接在细胞之间运输，这被定义为胞吞作用(paracytosis)。非吞噬途径包括网格蛋白(clathrin)介导的和小窝(caveolae)介导的内吞作用和巨胞饮作用，是通过口服途径吸收纳米制剂的最常见机制。
非口服施用可以提供多种益处，例如直接靶向到所需的作用部位和药物作用时间延长。已经针对纳米制剂对透皮施用进行了优化，例如固体脂质纳米颗粒(SLN)和NE，其特点是具有良好的生物相容性、较低的细胞毒性和理想的药物释放调节作用(Cappel和Kreuter,“Effect of nanoparticles on transdermal drug delivery.J Microencapsul8:369–374(1991))。鼻腔施用纳米制剂使它们能够通过内吞作用经由透粘膜途径或经由载体或受体介导的转运过程穿透鼻粘膜(Illum,“Nanoparticulate systems for nasaldelivery of drugs:a real improvement over simple systems？”J.Pharm.Sci 96:473–483(2007))，其中一个实例是鼻腔施用替扎尼定(tizanidine)的壳聚糖纳米颗粒，以提高小鼠的脑部渗透和药物功效(Patel等人,“Improved transnasal transport and brainuptake of tizanidine HCl-loaded thiolated chitosan nanoparticles foralleviation of pain,”J.Pharm.Sci 101:690–706(2012))。肺部施用可以提供较大的表面积并相对容易进入。粘液屏障、气管支气管区域中的代谢酶和肺泡中的巨噬细胞通常是药物渗透的主要屏障。颗粒大小是决定纳米制剂在支气管树中扩散的主要因素，纳米级区域中的颗粒更可能到达肺泡区域，直径在1至5μm之间的颗粒有望在细支气管中沉积(Musante等人,“Factors affecting the deposition of inhaled porous drugparticles,”J Pharm Sci 91:1590–1600(2002))。对于较大的颗粒，已经显示出吸收受限，这可能是由于无法穿过空气-血液屏障。颗粒可以逐渐释放药物，从而药物可以渗透到血流中，或者颗粒可以被肺泡巨噬细胞吞噬(Bailey和Berkland,“Nanoparticle formulationsin pulmonary drug delivery,”Med.Res.Rev.,29:196–212(2009))。
某些纳米制剂在吸收部位通过生物膜的渗透极小，对于这些纳米制剂，静脉注射施用可能是在体内获得有效分布的优选途径(Wacker,“Nanocarriers for intravenousinjection–The long hard road to the market,”Int.J.Pharm.,457:50–62.,2013)。
纳米制剂的分布可以根据所使用的递送系统、纳米制剂的特性、个体之间的变异性以及纳米制剂的药物流失率而变化很大。某些纳米颗粒，例如固体药物纳米颗粒(SDN)，能够改善药物吸收，这不需要它们完好无损地到达系统循环中。其他纳米颗粒在吸收过程中幸存，从而改变了所含药物的分布和清除率。
具有一定大小和组成的纳米制剂可以通过特征明确的过程(例如增强的渗透性和保留效应)在组织中扩散，而其他纳米制剂则在特定的细胞群中聚积，这使得一种纳米制剂可以靶向特定的器官。复杂的生物屏障可以保护器官免受外源性化合物的侵害，而血脑屏障(BBB)则是许多治疗剂的障碍。BBB中存在许多不同类型的细胞，包括内皮细胞、小胶质细胞、周细胞和星形胶质细胞，BBB表现出极为严格的紧密连接，以及高活性的外排机制，从而限制了大多数药物的渗透。通过BBB运输通常仅限于由特定转运蛋白携带的小的亲脂性分子和营养物质。调节纳米制剂向脑内扩散的最重要机制之一是通过脑毛细血管内皮细胞的内吞作用。
最近的研究已经将颗粒性质与纳米制剂的进入途径和在人类BBB内皮屏障中的加工过程相关联，表明未被包覆的纳米颗粒通过BBB的渗透有限，并且表面修饰会影响内吞作用的效率和机制(Lee等人,“Targeting rat anti-mouse transferrin receptormonoclonal antibodies through blood-brain barrier in mouse,”J.Pharmacol.Exp.Ther.292:1048–1052(2000))。因此，穿过BBB并递送本文所述的一种或多种化合物的表面修饰的纳米颗粒在本发明的范围内。
肝脏中的巨噬细胞是体内巨噬细胞总数的主要来源。肝脏中的枯否(Kupffer)细胞具有许多用于选择性吞噬被调理过的颗粒的受体(补体蛋白的受体和IgG片段可结晶部分的受体)。吞噬作用可以提供靶向巨噬细胞，并提供本文所述化合物的局部递送(即，在巨噬细胞内部的递送)的机制。
与聚乙二醇(PEG)相连的纳米颗粒与受体的相互作用极小，从而抑制了单核吞噬系统的吞噬(Bazile等人,“Stealth Me.PEG-PLA nanoparticles avoid uptake by themononuclear phagocytes system,”J.Pharm.Sci.84:493–498(1995))。
代表性的纳米制剂包括无机纳米颗粒、SDN、SLN、NE、脂质体、聚合物纳米颗粒和树枝状聚合物。本文所述的化合物可以包含在纳米制剂内部，或者在无机纳米颗粒和树枝状聚合物的一些情况下，化合物附着在表面上。也可以使用包含多于一种纳米制剂类别的元素的杂合纳米制剂。
SDN是不含脂质的纳米颗粒，它可以改善口服生物利用度和水溶性差的药物的暴露性(Chan,“Nanodrug particles and nanoformulations for drug delivery,”Adv.Drug.Deliv.Rev.63:405(2011))。SDN包含药物和稳定剂，它们是使用“自上而下(top-down)”(高压均质和湿磨)或自下而上(bottom-up)(溶剂蒸发和沉淀)方法生产的。
SLN由在室温下为固体的一种或多种脂质、乳化剂和水组成。使用的脂质包括但不限于甘油三酯、偏甘油酯、脂肪酸、类固醇和蜡。SLN最适合用于递送高度亲脂性药物。
在不混溶的液体中散布的小于1000nm的液滴被分类为NE。NE既用作疏水剂的载体又用作亲水剂的载体，并且可以口服、透皮、静脉内、鼻内和眼内施用。对于慢性疗法，口服施用可能是优选的，NE可以有效增强小分子、肽和蛋白质的口服生物利用度。
聚合纳米颗粒是固体颗粒，通常大小约为200-800nm，可以包括合成和/或天然聚合物，可以任选地将其聚乙二醇化以最大程度地减少吞噬作用。与传统制剂相比，聚合纳米颗粒可以提高药物和其他物质的生物利用度。它们的清除率取决于几个因素，包括聚合物的选择(包括聚合物大小、聚合物电荷和靶向配体)，大于100nm的带正电的纳米颗粒主要通过肝脏清除(Alexis等人,Factors affecting the clearance and biodistribution ofpolymeric nanoparticles.Mol Pharm 5:505–515(2008))。
树枝状聚合物是树状的纳米结构聚合物，直径通常为10–20nm。
脂质体是包括磷脂双层的球形囊泡。可以利用多种脂质，以一定程度控制降解水平。除口服施用外，脂质体还可以通过多种方式施用，包括静脉内施用(McCaskill等人,2013)、透皮施用(Pierre和Dos Santos Miranda Costa,2011)、玻璃体内施用(Honda等人,2013)以及通过肺施用(Chattopadhyay,2013)。脂质体可以与合成聚合物结合，以形成脂质-聚合物杂合纳米颗粒，从而延伸其靶向体内特定部位的能力。脂质体包裹的药物的清除率取决于药物的释放和脂质体的破坏(吞噬细胞免疫细胞摄取脂质体、聚集、pH敏感性分解等)(Ishida等人,“Liposome clearance,”Biosci Rep 22:197–224(2002))。
这些纳米颗粒制剂中的一种或多种可以用于跨血脑屏障和适当的其他位置将本文所述的活性剂递送至巨噬细胞。
控释制剂
在一个优选的实施方案中，活性化合物与载体一起制备，所述载体将保护化合物免于从体内快速消除，例如控释制剂，包括但不限于植入物和微囊化递送系统。可以使用可生物降解的、生物相容的聚合物，例如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。例如，肠溶包衣的化合物可用于保护胃酸的裂解。制备这种制剂的方法对于本领域技术人员来说是显而易见的。合适的材料也可以商购获得。
脂质体悬浮液(包括但不限于用针对病毒抗原的单克隆抗体靶向感染细胞的脂质体)也是优选的药学上可接受的载体。这些可以根据本领域技术人员已知的方法制备，例如，如美国专利号4,522,811(通过引用并入)所述。例如，脂质体制剂可以通过如下方法制备：将适当的脂质(例如硬脂酰磷脂酰乙醇胺、硬脂酰磷脂酰胆碱、花生四烯酰磷脂酰胆碱(arachadoyl phosphatidyl choline)和胆固醇)溶解在无机溶剂中，然后蒸发无机溶剂，在容器的表面上留下干燥的脂质薄膜。然后将活性化合物的水溶液引入容器中。然后用手旋转容器以从容器的侧面释放脂质材料并分散脂质聚集体，从而形成脂质体悬浮液。
用于描述本发明的术语是本领域技术人员通常使用和已知的。如本文所用，以下缩写具有所指示的含义：
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺
DME 二甲氧基乙烷
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
EDCI N-(3-二甲基氨基丙基)-N-乙基碳二亚胺盐酸盐
EtOAc 乙酸乙酯
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧化物六氟磷酸酯
HOBt 羟基苯并三唑
MeOH 甲醇
THF 四氢呋喃
X-phos 2-二环己基膦-2′,4′,6′-三异丙基联苯
IX.制备活性化合物的一般方法
容易地制备活性化合物的方法是本领域已知的，并且是由已知方法的选择性组合得到的。本文公开的化合物可以如下文详细描述或通过本领域技术人员已知的其他方法来制备。本领域的普通技术人员将理解，可以在不脱离本发明的精神的情况下进行细节的变化，并且决不限制本发明的范围。
各种反应方案总结如下。
方案1：化合物5的合成方法。
方案2：中间体4的替代合成方法。
方案3：化合物8和10的合成方法。
方案4：化合物8和10的替代合成方法。
方案5：通式15的化合物的合成方法。
方案6：通式16的化合物的合成方法。
方案7：通式17的化合物的合成方法。
方案8：通式22的化合物的合成方法。
方案9：通式22的化合物的替代合成方法。
式A的化合物可以由本领域普通技术人员使用以下文献中概述的方法：(a)Wang,L.；Sullivan,G.M.；Hexamer,L.A.；Hasvold,L.A.；Thalji,R.；Przytulinska,M.；Tao,Z.F.；Li,G.；Chen,Z.；Xiao,Z.；Gu,W.Z,；Xue,J.；Bui,M.H.；Merta,P.；Kovar,P.；Bouska,J.J.；Zhang,H.；Park,C.；Stewart,K.D.；Sham,H.L.；Sowin,T.J.；Rosenberg,S.H.；Lin,N.H.J.Med.Chem.,2007,50(17),4162–4176；b)Hasvold LA1,Wang L,Przytulinska M,Xiao Z,Chen Z,Gu WZ,Merta PJ,Xue J,Kovar P,Zhang H,Park C,Sowin TJ,RosenbergSH,Lin NH.Bioorg.Med.Chem.Lett.2008,18,2311-2315；c)Giannotti,D.；Viti,G.；Sbraci,P.；Pestellini,V.；Volterra,G.；Borsini,F.；Lecci,A.；Meli,A.；Dapporto,P.；Paoli,P.J.Med.Chem.,1991,34,1356–1362；c)Ramírez-Martínez,J.F.；González-Chávez,R.；Guerrero-Alba,R.；Reyes-Gutiérrez,P.E.；Martínez,R.；Miranda-Morales,M.；Espinosa-Luna,R.；González-Chávez,M.M.；Barajas-López,C.Molecules,2013,18,894-913并通过通用方案1-9完成。
在本文描述的方案中，如果中间体包括在某些步骤中可能干扰、分解或以其他方式转化的官能团，则可以使用合适的保护基团来保护此类官能团。这些步骤之后，可以对受保护的官能团(如果有的话)进行脱保护。
方案1：化合物5的合成方法。
化合物5可以例如通过方案1中所述的化学方法获得。通式1的化合物与通式2的适当取代的硝基苯胺在Cu和无机碱(例如K2CO3、Na2CO3或Cs2CO3)的存在下反应可以提供中间体3。在醇溶剂体系中在氢气存在下例如使用Pt/C还原硝基或在EtOAc中使用SnCl2还原硝基可得到通式4的化合物。化合物4可以在酸例如HCl或对甲苯磺酸的存在下环化(路线B)。或者，可以在碱性条件下用例如LiOH在水和THF的混合物中处理化合物4，得到酸中间体，然后可以在经典的肽条件下使用偶联剂例如HATU在有机碱(例如Et3N)存在下将其环化(路线A)。
方案2：中间体4的替代合成方法。
通式4的化合物也可以通过使通式1的化合物与通式6的二胺在Cu和无机碱例如K2CO3、Na2CO3或Cs2CO3的存在下反应来制备。
X＝卤素、OTf、OMes、OTos……
方案3：化合物8和10的合成方法。
通式8和10的化合物可以通过炔烃、烷基、烯烃、有机硼烷或有机锡烷衍生物在经典钯催化的Sonogashira、Heck、Suzuki或Stille偶联条件下的偶联反应从通式7或9的化合物获得，其中X是离去基团，例如卤素、三氟甲磺酸酯、甲磺酸酯或甲苯磺酸酯。
方案4：化合物8和10的替代合成方法。
或者，通式8和10的化合物可以通过通式7或9的化合物的硼化反应来制备，其中X是离去基团，例如卤素、三氟甲磺酸酯、甲磺酸酯或甲苯磺酸酯。然后，在经典的钯催化的Suzuki偶联条件下，中间体11和12可以与含有离去基团如卤素、三氟甲磺酸酯、甲磺酸酯或甲苯磺酸酯的芳基、杂芳基、烯烃、炔烃反应。
在一个实施方案中，R2和R3结合形成杂环，其可以包括五至七元环。
方案5：通式15的化合物的合成方法。
通式15的化合物可以通过在碱性条件下用例如LiOH在水和THF的混合物中处理从由上述化学方法制得的通式的酯制备，得到酸中间体，然后可以在经典的肽条件下使用偶联剂例如HATU在有机碱(例如Et3N)存在下与胺偶联。
方案6：通式16的化合物的合成方法。
通式16的化合物可通过在碱的存在下用胺化剂如O-(2,4-二硝基苯基)羟基胺处理而获得。
方案7：通式17的化合物的合成方法。
通式17的化合物可以通过用氧化剂例如mCPBA处理而获得。
方案8：通式22的化合物的合成方法。
通式22的化合物可以通过方案8中所述的化学方法获得。通式18的化合物与通式19的适当取代的苯胺在有机碱例如吡啶或三甲基胺的存在下反应可以提供中间体20。在醇溶剂体系中在氢气存在下例如使用Pt/C还原硝基或在EtOAc中使用SnCl2还原硝基可得到通式21的化合物。化合物21可以在Cu和无机碱例如K2CO3、Na2CO3或Cs2CO3存在下进行环化。
方案9：通式22的化合物的替代合成方法。
或者，通式22的化合物可以通过方案9中所述的化学方法获得。通式18的化合物与通式23的适当取代的苯胺在有机碱例如吡啶或三乙基胺的存在下反应可以提供中间体24。在醇溶剂体系中在氢气存在下例如使用Pt/C还原硝基或在EtOAc中使用SnCl2还原硝基可得到通式25的化合物。可以使用例如NaNO2、CF3COOH和NaN3进行25的叠氮化，以得到通式26的化合物。可以在高沸点溶剂例如二己醚中在高温下环化化合物26。
芳族环的取代反应
在以上所示的各种反应方案中，所述芳族环被各种R1和R2取代基取代。本领域已知如何在芳族环上提供取代基。例如，在期望在一个或两个芳族环上提供取代的情况下，亲电子芳族取代可用于提供期望的官能度。例如，可以使用Friedel-Crafts烷基化/芳基化/酰化反应添加烷基、芳基、杂芳基、烷芳基、芳基烷基、烯基、炔基和酰基。可以使用其他亲电芳族取代反应，例如以提供卤素，例如通过原位形成氯鎓或溴鎓离子并使它们与芳族环反应，或通过形成锍或硝鎓离子以提供磺酰基或硝基。
使用适当的卤代烷基结构部分和路易斯酸进行Friedel Crafts烷基化反应。所述烷基结构部分形成碳正离子，来自芳基环的电子与碳正离子形成键，从而在芳基环上带正电荷。然后，芳基环失去质子。以此方式可以添加烷基和烷芳基结构部分(例如苄基结构部分)。
Friedel Crafts的酰化作用相似，但使用酰卤(例如酰氯)将酮结构部分置于环上。所述酰卤可以是烷基酸，例如乙酸、丙酸、丁酸等，或者可以是芳族酸，例如苯甲酸、对甲苯甲酸等。
Friedel Crafts芳基化反应(也称为Scholl反应)是路易斯酸催化的带有两个芳基环的偶联反应。在偶联反应过程中失去的质子用作另外的催化剂。典型的试剂是二氯甲烷中的氯化铁(III)，二氯甲烷中的氯化铜(II)、PIFA和三氟化硼醚化物，在乙腈中的氯化钼(V)和四乙酸铅与BF3。
取代反应通常发生在胺基的邻位或对位以及硝基的间位位置。因此，取决于所需的官能度和位置，可能期望从胺基开始并放置取代基。因此，通常使用该化学方法将位置3、6和8官能化。可以通过将胺基氧化成硝基，从而导致间位取代，进行萘环在胺基的间位(即2位和7位)的取代。然后可以将硝基还原回胺基。
掺入氘：
预期在ROR调节剂的代谢位点用氘单次或多次置换氢(碳-氢键变为碳-氘键)会减慢代谢速率。这可以提供相对较长的半衰期，以及较慢的从身体清除的速率。预计治疗性ROR调节剂的缓慢代谢会为治疗候选物增加额外的优势，而其他物理或生化特性不会受到影响。
将氘掺入到有机衍生物中的方法是本领域技术人员众所周知的。代表性方法公开于Angew.Chem.Int.Ed.Engl.2007,46,7744-7765。因此，使用这些技术，可以在本文所述的ROR调节剂中提供一个或多个氘原子。
参考以下非限制性实施例将更好地理解本发明。
实施例1
化合物1和化合物34-46的合成。
4-氟-3-硝基苯甲酸甲酯(28)
将4-氟-3-硝基苯甲酸27(10g，54mmol)在室温下溶解在甲醇(200mL)和浓H2SO4(1mL)中。将反应混合物在80℃下搅拌过夜。反应完成后，将溶剂减压蒸发。将粗混合物用H2O(200ml)稀释，并用NaHCO3饱和溶液碱化。过滤沉淀的固体，用水(2×100mL)洗涤，并在真空下干燥，得到化合物28，为白色固体(10.75g，84％)；1H NMR(400MHz,DMSO-d6)：δ8.54(dd,J＝7.3,2.3Hz,1H),8.31(ddd,J＝8.8,4.3,2.3Hz,1H),7.73(dd,J＝11.1,8.7Hz,1H),3.90(s,3H)；13C NMR(101MHz,DMSO-d6):158.7,156.0,136.9,136.8(d,J＝10.8Hz),127.1(d,J＝1.6Hz),126.7(d,J＝3.9Hz),119.4(d,J＝21.7Hz),52.9；19F NMR(377MHz,DMSO)δ-111.97。
4-((2-(甲氧基羰基)苯基)氨基)-3-硝基苯甲酸甲酯(30)
在室温下，在惰性气氛下向4-氟-3-硝基苯甲酸甲酯28(1g，6.61mmol)在NMP(20mL)中的溶液中添加DIPEA(0.76ml，19.83mmol)和4-氟-3-硝基苯甲酸甲酯29(1.5g，9.92mmol)。将混合物在120℃搅拌14h，反应完成后，将混合物冷却至室温，用乙醚(20ml)稀释并搅拌1h。过滤得到的固体，用EtOAc洗涤(20mL)并真空干燥，得到化合物30，为黄色固体(996mg，45％)；1H NMR(400MHz,DMSO-d6):δ11.15(s,1H),8.66(d,J＝2.1Hz,1H),8.09–7.96(m,2H),7.71–7.61(m,2H),7.59(d,J＝9.0Hz,1H),7.29(ddd,J＝8.2,5.9,2.1Hz,1H),3.87(s,6H)；13C NMR(101MHz,DMSO):δ166.6,164.5,142.7,139.7,135.4,134.7,133.9,131.5,128.0,124.2,121.9,120.4,120.0,117.8,52.5,52.3。
3-氨基-4-((2-(甲氧基羰基)苯基)氨基)-苯甲酸甲酯(31)
将4-((2-(甲氧基羰基)苯基)氨基)-3-硝基苯甲酸甲酯30(2.5g，7.5mmol)和10％Pd/C(1.25g，50％湿)的MeOH溶液在室温下在氢气气氛中搅拌16小时。反应完成后，将混合物通过硅藻土过滤并用20％MeOH/DCM(250mL)洗涤。将滤液浓缩，并将粗残余物通过快速柱色谱法纯化(AcOEt/己烷3/7)，得到化合物31，为黄色固体(1.4g，62％)；1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.91(d,J＝8.4Hz,1H),7.52–7.36(m,2H),7.21(s,2H),6.95(d,J＝8.4Hz,1H),6.88–6.72(m,1H),5.19(s,2H),3.85(s,3H),3.80(s.3H)；13C NMR(101MHz,DMSO)δ167.9,166.3,146.7,142.2,134.3,131.2,130.6,125.5,121.9,118.1,117.7,116.2,114.9,112.3,51.9,51.8。
3-氨基-4-((2-羧基苯基)氨基)苯甲酸(32)
在室温下，向3-氨基-4-((2-(甲氧基羰基)苯基)氨基)苯甲酸甲酯31(1.4g，4.66mmol)在THF：H2O(2.5/1，105ml)的混合物中的溶液中添加一水合氢氧化锂(1.75g，41.9mmol)。将反应混合物在65℃下搅拌5小时，随后在真空下除去挥发物。用2N HCl将残余物的pH降低至4。过滤沉淀的固体，用水(10mL)洗涤，并在真空下干燥，得到化合物32，为白色固体(1g，80％)。1H NMR(400MHz,DMSO-d6)δ12.64(s,2H),9.20(s,1H),7.89(d,J＝7.9Hz,1H),7.44–7.31(m,2H),7.18(s,2H),6.91(d,J＝8.5Hz,1H),6.76(t,J＝7.5Hz,1H),5.06(s,2H)；13C NMR(101MHz,DMSO)δ169.8,167.4,147.3,142.1,134.0,131.7,130.4,126.6,121.9,118.4,117.3,116.5,114.5,112.8。
11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-8-甲酸(33)
将化合物32(1g，3.67mmol)和CDI(2.39g，14.6mmol)的THF(40mL)溶液在室温下在惰性气氛下搅拌24h。反应完成后，在真空下除去挥发物。用2N HCl将残余物的pH调节至2。过滤沉淀的固体，用戊烷(10mL)洗涤，并在真空下干燥，得到化合物33，为淡绿色固体(746mg，80％)。1H NMR(400MHz,DMSO-d6)12.66(s,1H),9.93(s,1H),8.28(s,1H),7.70(dd,J＝7.9,1.7Hz,1H),7.57–7.49(m,2H),7.36(td,J＝7.9,1.7Hz,1H),7.02(dd,J＝17.0,8.1Hz,2H),6.91(t,J＝7.4Hz,1H)；13C NMR(101MHz,DMSO)δ167.4,166.7,148.8,143.8,133.5,132.3,129.2,126.0,125.0,122.5,122.2,121.1,119.4,119.2,SM(IS):m/z:255.4[M+1]
通用程序I
在0℃下，在惰性气氛下向化合物33(100mg，0.393mmol)的DMF(5ml)溶液中加入EDCI、HCl(121mg，0.629mmol)、HOBt(85mg，6.29mmol)、胺(0.511mmol)和DIPEA(205ml，0.117mmol)。然后将反应混合物在室温下搅拌16-24小时。反应完成后，加入水。过滤粗固体，并用水洗涤。粗残余物通过硅胶色谱法(DCM/甲醇)纯化，得到所需化合物。
8-(4-苄基哌啶-1-羰基)-10,11a-二氢-4aH-二苯并[b,e][1,4]二氮杂卓-11(5H)-酮(化合物1)
按照通用程序I，由4-苄基哌啶(91ml，0.511mmol)制备化合物1。柱色谱法：DCM/甲醇(95:5)；淡黄色固体(111mg，68％)；1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.06(s,1H),7.68(d,J＝7.8Hz,1H),7.34(t,J＝7.8Hz,1H),7.27(t,J＝7.8Hz,2H),7.16(d,J＝7.8Hz,3H),7.05-6.99(m,4H),6.89(d,J＝7.8Hz,1H),4.34(s,1H),3.67(s,1H),2.78(s,2H),2.52(s,2H),1.75(s,1H),1.56(s,2H),1.17–1.02(m,2H)；13C NMR(101MHz,DMSO-d6)δ168.2,167.6,149.6,140.7,140.0,133.4,132.2,130.6,129.3,129.0,128.1,125.8,123.4,122.5,120.9,120.0,119.4,119.1,42.1,37.5,31.6；SM(IS):412.5m/z:[M+1]；HRMS(ESI)[M+H]+C26H26N3O2计算值:412.1947，实测值:412.2018。
8-(4-苯基哌嗪-1-羰基)-5H-二苯并[b,e][1,4]二氮杂卓-11(10H)-酮(34)
按照通用程序I，由4-苯基哌嗪(77ml，0.511mmol)制备化合物34。柱色谱法：DCM/甲醇(95:5)；米色固体(100mg，64％)；1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.12(s,1H),7.70(d,J＝7.7Hz,1H),7.37(t,J＝7.6Hz,1H),7.23(t,J＝7.9Hz,2H),7.06(d,J＝2.6Hz,3H),7.01(d,J＝8.0Hz,1H),6.97-6.93(m,3H),6.82(t,J＝7.2Hz,1H),3.72–3.52(m,4H),3.15(s,4H)；13C NMR(101MHz,DMSO-d6)δ168.4,167.6,150.8,149.5,141.0,133.4,132.2,129.8,129.4,129.0,123.8,122.4,120.9,120.4,119.4,119.4,119.1,115.9,48.2；SM(IS):399.5m/z:[M+1]；C24H23N4O2的HRMS(ESI)[M+H]+计算值：399.1810，实测值399.1812
N-壬基-11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-8-甲酰胺(35)
按照通用程序I，由壬胺(93μl，0.511mmol)制备化合物35。将反应混合物用水淬灭，并用乙酸乙酯(3×5mL)萃取。合并的有机层经硫酸镁干燥并减压浓缩，最后通过柱色谱法纯化，用DCM/甲醇(99∶1至95/5)洗脱；黄色固体(70mg，47％)；1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.24(t,J＝5.4Hz,1H),8.13(s,1H),7.69(dd,J＝7.9,1.6Hz,1H),7.47–7.39(m,2H),7.39–7.32(m,1H),7.00(dd,J＝7.9,5.4Hz,2H),6.91(t,J＝7.9Hz,1H),3.20(q,J＝6.6Hz,2H),1.49(d,J＝8.0Hz,2H),1.30–1.22(m,12H),0.85(t,J＝6.6Hz,3H)；13C NMR(101MHz,DMSO-d6)δ167.5,165.3,149.4,142.4,133.4,132.2,129.5,129.2,123.2,122.4,121.0,120.9,119.1,119.0,31.3,29.1,29.0,28.8,28.7,26.5,22.1,14.0；SM(IS):380.2m/z:[M+1]；C23H30N3O2的HRMS(ESI)[M+H]+计算值：380.2327，实测值：380.2332。
8-(4-苄基哌嗪-1-羰基)-5H-二苯并[b,e][1,4]二氮杂卓-11(10H)-酮(36)
按照通用程序I，由1-苄基哌嗪(89ml，0.511mmol)制备化合物36。柱色谱法：DCM/甲醇(99:1至95/5)；黄色固体(42mg，26％)；1H NMR(400MHz,DMSO-d6)9.92(s,1H),8.09(s,1H),7.69(dd,J＝7.9,1.7Hz,1H),7.40–7.27(m,5H),7.25(td,J＝5.9,2.5Hz,1H),7.08–6.93(m,4H),6.91(t,J＝7.9Hz,1H),3.50(s,4H),3.36(s,2H),2.36(s,4H)；13C NMR(101MHz,DMSO-d6)168.3,167.6,149.5,141.0,137.8,133.4,132.2,130.0,129.3,128.9,128.2,127.0,123.7,122.4,120.9,120.3,119.4,119.1,61.9,52.6；SM(IS):413.5m/z:[M+1]；C25H25N4O2的HRMS(ESI)[M+H]+计算值：413.1899，实测值：413.1970。
8-(4-(4-氟苄基)哌啶-1-羰基)-5H-二苯并[b,e][1,4]二氮杂卓-11(10H)-酮(37)
按照通用程序I，由4-(4-氟苄基)哌啶(99mg，0.511mmol)制备化合物37。柱色谱法：DCM:MeOH(99/1至95/5)；黄色固体(74mg，43％)；1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.07(s,1H),7.69(dd,J＝8.0,1.7Hz,1H),7.36(ddd,J＝8.0,7.2,1.7Hz,1H),7.24–7.19(m,2H),7.13–7.07(m,2H),7.04–6.95(m,4H),6.91(ddd,J＝8.0,7.2,1.7Hz,1H),4.36(s,1H),3.68(s,1H),2.86(s,2H),2.52(s,2H),1.75(s,1H),1.56(s,2H),1.11(qd,J＝12.3,4.2Hz,2H).13C NMR(101MHz,DMSO-d6):δ133.4,132.2,130.7(d,J＝7.8Hz),123.4,120.9,120.0,119.3,119.1,114.8(d,J＝20.9Hz),41.1,37.5.19F NMR(377MHz,DMSO-d6):δ-117.51(s).SM(IS):430.5m/z:[M+1]；C26H25FN3O2的HRMS(ESI)[M+H]+计算值：430.1853，实测值：430.1926。
8-(吗啉-4-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(38)
按照通用程序I，由吗啉(44ml，0.511mmol)制备化合物38。16小时后，将反应用水淬灭，并用乙酸乙酯(3×5mL)萃取。合并的有机层经硫酸镁干燥并减压浓缩，通过柱色谱法纯化，用DCM/甲醇(99∶1至95/5)洗脱；黄色固体(54mg，43％)；1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.10(s,1H),7.70(dd,J＝7.9,1.6Hz,1H),7.36(ddd,J＝8.6,7.9,1.7Hz,1H),7.06–6.94(m,4H),6.96–6.87(m,1H),3.58(d,J＝5.0Hz,4H),3.47(s,4H)；13C NMR(101MHz,DMSO-d6):δ168.5,167.6,149.5,141.1,133.4,132.2,129.6,129.4,123.8,122.4,120.9,120.5 119.4,119.1,66.2,40.1.SM(IS):324.5m/z:[M+1]；HRMS(ESI)C18H18N3O的[M+H]+计算值:324.1270,实测值:324.1341
N-(3-(1H-咪唑-1-基)丙基)-11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-8-甲酰胺(39)
按照通用程序I，由3-(1H-咪唑-1-基)丙烷-1-胺(0.511mmol)制备化合物39。16小时后，加入30ml水，并将混合物用20ml乙酸乙酯萃取两次。合并的有机层用MgSO4干燥，过滤并在真空下蒸发。粗固体通过柱色谱法纯化，用DCM/甲醇(99∶1至95/5)洗脱；黄色固体(40mg，28％)。1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.34(t,J＝5.6Hz,1H),8.15(s,1H),7.70(dd,J＝7.9,1.7Hz,1H),7.65(d,J＝1.3Hz,1H),7.53–7.41(m,2H),7.36(ddd,J＝8.7,7.2,1.7Hz,1H),7.21(d,J＝1.3Hz,1H),7.08–6.97(m,2H),6.93–6.87(m,2H),4.00(t,J＝6.9Hz,2H),3.19(q,J＝6.9Hz,2H),1.93(p,J＝6.9Hz,2H),13C NMR(101MHz,DMSO-d6):δ167.5,165.7,149.3,142.5,137.3,133.4,132.2,129.3,129.2,128.4,123.3,122.4,121.0,121.0,119.3,119.1,119.0,43.7,36.4,30.8.SM(IS):362.4m/z:[M+1]；C20H20N5O2的HRMS(ESI)[M+H]+计算值:362.1539,实测值:362.1609
8-(4-(2-氟苄基)哌啶-1-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(40)
按照通用程序I，由4-(2-氟苄基)哌啶(99mg，0.511mmol)制备化合物40。柱色谱法：DCM:MeOH(99/1至95/5)；黄色固体(135mg，80％)；1H NMR(400MHz,DMSO-d6):δ9.92(s,1H),8.08(s,1H),7.70(d,J＝7.8Hz,1H),7.36(t,J＝7.6Hz,1H),7.27(d,J＝8.6Hz,2H),7.14(q,J＝7.3Hz,2H),7.00(t,J＝5.9Hz,4H),6.92(t,J＝7.4Hz,1H),4.35(s,1H),3.69(s,1H),2.75(s,2H),2.58(d,J＝7.0Hz,2H),1.79(s,1H),1.58(s,2H),1.15(q,J＝12.5Hz,2H)；13C NMR(101MHz,DMSO-d6)δ168.3,167.6,161.8,159.4,149.6,140.8,133.4,132.2,131.7(d,J＝5.1Hz),130.6,129.3,128.1(d,J＝8.3Hz),126.6(d,J＝15.9Hz),124.2(d,J＝3.3Hz),123.4,122.5,120.9,120.0,119.4,119.1,115.1(d,J＝22.3Hz),36.6,35.0,31.7.19F NMR(377MHz,DMSO-d6)δ-118.26.,SM(IS):430.1m/z:[M+1]；C26H24FN3O2的HRMS(ESI)[M+H]+计算值:430.1853,实测值:430.1927
8-(哌啶-1-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(41)
按照通用程序I，由哌啶(58ml，0.511mmol)制备化合物41。24小时后，加入30ml水，并将混合物用20ml乙酸乙酯萃取两次。合并的有机层用MgSO4干燥，过滤并在真空下浓缩。粗固体通过柱色谱法纯化，用DCM/甲醇(99∶1至95/5)洗脱；黄色固体(20mg，16％)。1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.07(s,1H),7.69(dd,J＝7.9,1.7Hz,1H),7.40–7.33(m,1H),7.05–6.96(m,4H),6.95–6.88(m,1H),3.42-3.31(m,4H),1.60(q,J＝5.6Hz,2H),1.54–1.41(m,4H).13C NMR(101MHz,DMSO)δ168.2,167.7,149.6,140.7,133.4,132.2,130.7,129.4,123.4,122.5,120.9,120.0,119.4,119.1,25.7,24.7；C19H20N3O2的HRMS(ESI)[M+H]+计算值:322.1477，实测值：322.1548
8-(4-苯基哌啶-1-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(42)
按照通用程序I，由4-苯基哌啶(82mg，0.511mmol)制备化合物42。柱色谱法：DCM:MeOH(99/1至95/5)；黄色固体(67mg，43％)；1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.09(s,1H),7.70(dd,J＝7.9,1.7Hz,1H),7.38–7.32(m,1H),7.32–7.26(m,4H),7.21(d,J＝7.0Hz,1H),7.08–7.02(m,3H),7.00(dd,J＝8.1,1.1Hz,1H),6.94–6.88(m,1H),4.71–4.39(m,1H),3.95–3.66(m,1H),3.11–2.98(s,1H),2.80(t,J＝12.0Hz,2H),1.98–1.73(m,2H),1.61(td,J＝12.6,4.1Hz,2H).SM(IS):398.2m/z:[M+1]；
8-(4-苯乙基哌啶-1-羰基)5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(43)
按照通用程序I，由4-苯乙基哌啶(96mg，0.511mmol)制备化合物43。柱色谱法：DCM/甲醇(99/1至95/5)；黄色固体(67mg，40％)；1H NMR(400MHz,DMSO-d6 9.92(s,1H),8.07(s,1H),7.69(dd,J＝7.9,1.7Hz,1H),7.36(ddd,J＝8.5,7.9,1.7Hz,1H),7.28(t,J＝7.9Hz,2H),7.23–7.14(m,3H),7.03-6.97(d,J＝7.0Hz,4H),6.95–6.89(m,1H),4.38(s,1H),3.69(s,1H),2.90(s,2H),2.60(t,J＝7.5Hz,3H),1.73(s,2H),1.52(d,J＝7.4Hz,3H),1.22–0.99(m,H).13C NMR(101MHz,DMSO-d6)168.6,168.11,150.0,142.7,141.2,133.9,132.6,131.1,129.8,128.7,128.7,126.1,123.8,122.9,121.4,120.5,119.8,119.6,4,38.3,35.4,32.6.SM(IS):426.2m/z:[M+1]。
N-(1-苄基哌啶-4-基)-11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-8-甲酰胺(44)
按照通用程序I，由1-苄基-4-氨基哌啶(104ml，0.511mmol)制备化合物44。柱色谱法：DCM/甲醇(99/1至95/5)；黄色固体(60mg，35％)；1H NMR(400MHz,DMSO-d6)9.89(s,1H),8.14(s,1H),8.06(d,J＝7.6Hz,1H),7.69(dd,J＝7.9,1.6Hz,1H),7.45(d,J＝7.0Hz,2H),7.39–7.28(m,5H),7.27-7.23(m,1H),7.00(t,J＝7.9Hz,1H),6.95–6.85(m,1H),3.73(d,J＝7.0Hz,1H),3.46(s,2H),2.81(d,J＝9.8Hz,2H),2.01(s,2H),1.75(d,J＝12.4Hz,2H),1.56(td,J＝11.8,3.6Hz,2H)；13C NMR(101MHz,DMSO-d6):168.0,165.3,149.8,142.9,139.1,133.8,132.7,129.9,129.6,129.2,128.6,127.3,123.9,122.8,121.5,121.4,119.6,119.4,62.6,52.7,47.3,32.0.SM(IS):427.3m/z:[M+1]。
8-(4-苯甲酰基哌啶-1-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(45)
按照通用程序I，由4-苄甲酰基哌啶(89ml，0.511mmol)制备化合物45。柱色谱法：DCM/甲醇(99/1至95/5)；黄色固体(114mg，68％)；1H NMR(400MHz,DMSO-d6)9.93(s,1H),8.09(s,1H),8.01(d,J＝7.7Hz,2H),7.74–7.61(m,2H),7.55(t,J＝7.5Hz,2H),7.42–7.31(m,1H),7.02(d,J＝7.4Hz,4H),6.91(t,J＝7.5Hz,1H),4.40(s,1H),3.86–3.65(m,1H),3.08(s,4H),1.82(s,2H),1.52(d,J＝13.8Hz,3H),13C NMR(101MHz,DMSO-d6):δ201.7,168.4,167.6,149.5,140.8,135.4,133.4,133.26,132.2,130.3,129.3,128.8,128.2,123.5,122.4,120.9,120.0,119.4,119.1,42.4,28.5；SM(IS):426.2m/z:[M+1]。
8-(4-(3-氟苄基)哌啶-1-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(46)
按照通用程序I，用4-(3-氟苄基)哌啶盐酸盐(115mg，0.511mmol)制备化合物46。柱色谱法：DCM:MeOH(99/1至95/5)；黄色固体(90mg，53％)；1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.07(s,1H),7.69(dd,J＝7.9,1.7Hz,1H),7.38–7.27(m,2H),7.03–6.96(m,7H),6.93–6.88(m,1H),4.35(s,1H),3.73(s,1H),2.78(s,2H),2.54(d,J＝7.1Hz,2H),1.87(s,1H),1.55(s,2H),1.11(qd,J＝12.1,4.1Hz,2H),19F NMR(377MHz,DMSO-d6)δ-113.89(s),SM(IS):430.1m/z:[M+1]；
方案11：化合物47-49的合成。
8-(4-苄基哌啶-1-羰基)-10-甲基-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(47)
将化合物1(100mg，0.243mmol)溶解在1ml的DMF中，然后在室温下加入Cs2CO3(158mg，0.486mg)，接着加入MeI(16ml，0.267mmol)。将反应混合物在室温搅拌过夜，然后用H2O(20ml)稀释。过滤获得的固体，用5ml的H2O洗涤，然后通过硅胶柱色谱法(DCM/甲醇(99∶1))纯化，得到化合物47，为白色固体(80mg，78％)。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.67(dd,J＝7.9,1.7Hz,1H),7.40–7.33(m,1H),7.32–7.25(m,3H),7.20–7.12(m,4H),7.12–7.06(m,2H),7.00–6.95(m,1H),4.50–4.27(m,1H),3.80–3.56(m,1H),3.61(s,3H),3.10–2.82(m,1H),2.72-2.70(m,1H),2.53(s,2H),1.80–1.74(m,1H),1.67–1.47(m,2H),1.25–1.02(m,2H)；13C NMR(101MHz,DMSO)δ168.1,167.5,151.2,144.8,140.0,134.6,132.6,132.3,131.5,129.0,128.2,125.8,124.3,123.8,122.0,121.5,119.9,118.8,42.1,40.15,37.7,37.5,31.5.SM(IS):426.2m/z:[M+1]；C27H28N3O2的HRMS(ESI)[M+H]+计算值:426.2103,实测值:426.2176。
8-(4-苄基哌啶-1-羰基)-10-丁基-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(48)
将化合物1(40mg，0.097mmol)溶解在0.5ml的DMF中，然后在室温下加入NaH(5mg，0.194mg)，接着加入BuI(12ml，0.106mmol)。将反应混合物在室温下搅拌过夜。将混合物用H2O(20ml)稀释。过滤获得的固体，用5ml的H2O洗涤，并通过硅胶柱色谱法(DCM/甲醇(99∶1))纯化，得到化合物48，为白色固体(22.5mg，50％)；1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.68(dd,J＝7.8,1.7Hz,1H),7.43–7.37(m,2H),7.37–7.31(m,2H),7.24(ddd,J＝8.3,5.9,1.9Hz,4H),7.14(ddd,J＝16.2,8.2,1.5Hz,2H),7.03(ddd,J＝8.1,7.3,1.2Hz,1H),4.57–4.36(m,1H),4.08(s,2H),3.80–3.56(m,1H)3.10–2.86(m,2H),2.59(s,2H),1.88–1.77(m,1H),1.72–1.55(m,2H),1.50(dt,J＝14.2,6.8Hz,2H),1.32(dq,J＝14.2,7.3Hz,2H),1.26–1.15(m,2H),0.86(t,J＝7.3Hz,3H)。SM(IS):468.1m/z:[M+1]。
10-苄基-8-(4-苄基哌啶-1-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(49)
将化合物1(40mg，0.097mmol)溶解在0.5ml的DMF中，然后在室温下加入Cs2CO3(63mg，0.191mmol)，接着加入苄基溴(13ml，0.106mmol)。将反应混合物在室温搅拌过夜，然后用H2O(20ml)稀释。过滤获得的固体，用5ml的H2O洗涤，并通过硅胶柱色谱法(DCM/甲醇(99∶1))纯化，得到化合物49，为白色固体(38mg，80％)；1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.69(dd,J＝7.8,1.5Hz,1H),7.39(ddd,J＝8.5,7.3,1.6Hz,1H),7.35–7.24(m,7H),7.22–7.13(m,4H),7.16–7.07(m,2H),7.05–6.96(m,2H),5.27(s,2H),4.54–4.06(m,1H),2.94–2.50(m,1H),2.48(d,J＝6.7Hz,1H),1.77–1.65(m,1H),1.61–1.38(m,2H),1.27–1.23(m,1H),1.04–0.97(m,1H),0.90–0.84(m,1H)。SM(IS):502.6m/z:[M+1]。
化合物51和52的合成。
8-(4-苄基哌啶-1-羰基)-5-甲基-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(51)
按照通用程序I，由化合物50(120mg，0.447mmol，WO2015138895)和4-苄基哌啶(104ml，0.581mmol)制备化合物51。柱色谱法：DCM/甲醇(99:1)；白色固体(113mg，59％)；1HNMR(400MHz,DMSO-d6)δ10.30(s,1H),7.64(dd,J＝7.7,2.0Hz,1H),7.50(ddd,J＝8.2,7.3,1.8Hz,1H),7.27(dd,J＝8.3,6.5Hz,2H),7.24–7.14(m,5H),7.13–7.07(m,2H),7.04(d,J＝2.0Hz,1H),4.45-4.40(m,1H),3.66-3.6(m,1H),3.28(s,3H),2.99–2.82(m,1H),2.76–2.63(m,2H),2.52(s,1H),1.82–1.71(m,1H),1.69–1.45(m,2H),1.20–1.03(m,2H)；13C NMR(101MHz,DMSO-d6)δ:168.2,168.0,152.4,145.0,140.0,132.9,132.1,131.7,131.0,129.0,128.1,126.7,125.8,123.3,122.8,119.8,119.0,117.7,42.1,40.15,39.94,,37.8,37.5,31.9；SM(IS):426.1m/z:[M+1]；
8-(4-苄基哌啶-1-羰基)-5,10-二甲基-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(52)
将化合物51(50mg，0.117mmol)溶解在1ml的DMF中，然后在室温下加入Cs2CO3(76mg，0.235mg)，接着加入MeI(14ml，0.235mmol)。将反应混合物在室温搅拌2小时，然后用H2O(20ml)稀释。过滤获得的固体，用5ml的H2O洗涤，并通过硅胶柱色谱法(DCM/甲醇(99∶1))纯化，得到化合物52，为白色固体(33mg，65％)；1H NMR(400MHz,DMSO-d6)δ7.62(dd,J＝7.7,1.7Hz,1H),7.46(ddd,J＝8.7,7.7,1.9Hz,1H),7.33(d,J＝1.9Hz,1H),7.31–7.24(m,3H),7.20–7.14(m,5H),7.09(td,J＝7.5,1.0Hz,1H),4.53–4.23(m,1H),3.60–3.57(m,1H),3.43(s,3H),3.35(s,3H),2.99–2.93(m,1H),2.72–2.63(m,1H),2.52(s,2H),1.85–1.69(m,1H),1.68–1.43(m,2H),1.20–1.05(m,2H)；13C NMR(101MHz,DMSO)δ167.8,167.5,153.0,147.9,140.0,136.5,132.4,131.5,129.0,128.1,126.6,125.8,124.2,122.8,121.7,118.7,116.6,42.0,,37.4,37.4,37.0,31.9；SM(IS):m/z:440.5[M+1]；
化合物58的合成。
2-((2-氨基-4-(甲氧基羰基)苯基)氨基)-5-溴苯甲酸甲酯(55)
向3,4-二氨基苯甲酸甲酯54(2.051g，6.01mmol)在氯苯(20mL)中的溶液中加入5-溴-2-碘苯甲酸甲酯53(1g，6.01mmol)、K2CO3(0.87g，6.30mmol)和Cu(0.382g，6.01mmol)。将所述混合物加热回流18小时。趁热，将混合物通过硅藻土薄层过滤，并将滤饼用二氯甲烷洗涤。浓缩滤液，并将粗产物通过硅胶快速色谱纯化，用10％至100％CH2Cl2/己烷梯度洗脱，得到标题化合物55(1.1g，50％)。1H NMR(400MHz,氯仿-d)δ9.14(bs,1H),8.09(d,J＝2.4Hz,1H),7.49(s,1H),7.43(d,J＝8.2Hz,1H),7.38(dd,J＝9.0,2.5Hz,1H),7.21(d,J＝8.2Hz,1H),6.72(d,J＝9.0Hz,1H),3.93(s,3H),3.90(s,3H)。C16H15BrN2O4的LR-MS计算值378.02，实测值379.3,381.3
2-溴-11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-8-甲酸甲酯(56)
向在甲醇(35mL)中的化合物55(0.72g，1.9mmol)中加入浓HCl(7mL)，并将混合物加热至回流过夜。冷却至室温后，将反应混合物过滤并将滤饼用水洗涤以产生标题化合物56(0.63g，96％)。1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.52(s,1H),7.78(d,J＝2.5Hz,1H),7.59–7.52(m,3H),7.05(d,J＝8.2Hz,1H),6.96(d,J＝8.6Hz,1H),3.80(s,3H)。C15H11BrN2O3的LR-MS计算值345.99，实测值347.0,349.0。
2-溴-11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-8-甲酸(57)
在室温下，向化合物4(0.6g，1.7mmol)在THF∶H2O(7∶3，45mL)中的搅拌溶液中加入氢氧化锂一水合物(0.435g，10.4mmol)。将所得溶液在65℃搅拌4小时。通过TLC监测反应，反应完成后，真空除去挥发物。用2N HCl将残余物的pH酸化至约4。过滤沉淀的固体，用水(20mL)洗涤，并在真空下干燥，得到化合物5(0.570g，99％)。1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),10.00(s,1H),8.62(s,1H),7.70(d,J＝2.5Hz,1H),7.50–7.43(m,3H),7.04(d,J＝8.3Hz,1H),6.99(d,J＝8.7Hz,1H)。C19H9BrN2O3的LR-MS计算值331.97，实测值333.3,335.3
8-(4-苄基哌啶-1-羰基)-2-溴-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(58)
向化合物57(0.3g，0.90mmol)在5ml的DMF中的溶液中添加N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDCI)(0.276g，1.44mmol)、N-羟基苯并三唑(HOBt)(0.194g，1.44mmol)、4-苄基哌啶(0.205mL，1.17mmol)，然后加入DIPEA(0.470mL，2.70mmol)。将反应混合物在室温搅拌16小时，用水淬灭，然后用乙酸乙酯萃取。合并的有机层用盐水洗涤，经硫酸钠干燥并在真空下浓缩。然后将残余物悬浮在3mL乙酸乙酯中，之后添加30mL己烷。过滤沉淀物并用己烷(10mL)洗涤，得到标题化合物58(0.430g，97％)。1H NMR(400MHz,甲醇-d4)δ7.85(d,J＝2.4Hz,1H),7.44(dd,J＝8.6,2.5Hz,1H),7.28–7.23(m,2H),7.18–7.14(m,3H),7.06–6.97(m,3H),6.85(d,J＝8.6Hz,1H),4.63–4.44(m,1H),3.88–3.63(m,1H),3.11–2.92(m,1H),2.91–2.08(m,1H),2.86–2.69(m,1H),2.56(d,J＝5.7Hz,2H),1.91–1.54(m,3H),1.29–1.11(m,2H)。C26H24BrN3O2的LR-MS计算值489.10，实测值490.0,491.9
化合物59的合成。
8-(4-苄基哌啶-1-羰基)-2-乙烯基-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(59)
将化合物58(0.1g，0.204mmol)和乙烯基三氟硼酸钾(36mg，0.265mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)(0.030，0.04mmol)和K3PO4·3H2O(0.143g，0.674mmol)的混合物在DME：H2O(2：1，4mL)中加热至回流16小时。冷却后，将反应混合物在乙酸乙酯和水之间分配。乙酸乙酯层用盐水洗涤，用硫酸镁干燥，过滤并浓缩。将残余物通过硅胶快速柱色谱法纯化，使用CH2Cl2∶MeOH洗脱，得到标题化合物59(50mg，50％)。1H NMR(400MHz,甲醇-d4)δ7.82(d,J＝2.2Hz,1H),7.47(dd,J＝8.4,2.2Hz,1H),7.29-7.24(m,2H),7.19–7.15(m,3H),7.06–6.98(m,3H),6.91(d,J＝8.4Hz,1H),6.65(dd,J＝17.6,11.0Hz,1H),5.68(dd,J＝17.6,0.9Hz,1H),5.16(dd,J＝10.9,0.9Hz,1H),4.62-4.45(m,1H),3.85-3.70(m,1H),3.12–2.94(m,1H),2.86-2.69(m,1H),2.58(d,J＝7.1Hz,2H),1.88–1.55(m,3H),1.29–1.11(m,2H)。C28H27N3O2的LR-MS计算值437.21，实测值438.5
化合物60-66的合成。
8-(4-苄基哌啶-1-羰基)-2-(吡啶-3-基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(60)
将化合物58(0.025g，0.051mmol)和3-吡啶硼酸1,3-丙二醇酯(0.013，0.076mmol)、Pd2(dba)3CHCl3(5.2mg，0.005mmol)、X-Phos(14.6mg，0.030mmol)和K3PO4 3H2O(0.035g，0.168mmol)的混合物在DME：H2O(2：1，4mL)中加热至回流48小时。反应冷却至室温后，将混合物在乙酸乙酯和水之间分配。乙酸乙酯层用盐水洗涤，在硫酸镁上干燥，过滤并浓缩。将残余物通过硅胶快速柱色谱法纯化，使用CH2Cl2∶MeOH洗脱，得到标题化合物59(19mg，78％)。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.83(d,J＝2.6Hz,1H),8.53(dd,J＝4.8,1.6Hz,1H),8.32(s,1H),8.03–7.99(m,2H),7.76(dd,J＝8.4,2.4Hz,1H),7.48–7.44(m,1H),7.30–7.27(m,2H),7.20–7.12(m,4H),7.05–6.99(m,3H),4.50–4.18(m,1H),3.85–3.50(m,1H),3.05–2.58(m,2H),2.53(d,J＝7.7Hz,2H),1.84–1.71(m,1H),1.70–1.41(m,2H),1.18–1.06(m,2H)。C31H28N4O2的LR-MS计算值488.22，实测值489.2
4-(8-(4-苄基哌啶-1-羰基)-11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-2-基)苯甲酰胺(61)
通过用4-氨基羰基苯基硼酸代替3-吡啶硼酸1,3-丙二醇酯，按照制备化合物60所用的化学方法合成化合物61(63％收率)。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.31(s,1H),8.09–7.91(m,4H),7.77(dd,J＝8.5,2.4Hz,1H),7.69(d,J＝8.5Hz,2H),7.38(s,1H),7.32–7.25(m,2H),7.22–7.09(m,4H),7.07–6.97(m,3H),4.58–4.14(m,1H),3.85–3.54(m,1H),3.05–2.53(m,4H),1.87–1.69(m,1H),1.68–1.43(s,2H),1.19–1.06(m,2H)。C33H30N4O3的LR-MS计算值530.23，实测值531.2
4-(8-(4-苄基哌啶-1-羰基)-11-氧-10,11-二氢-5H-二苯并[b,e][1,4]二氮杂卓-2-基)苯甲酸甲酯(62)
通过用4-甲氧基羰基苯基硼酸代替3-吡啶硼酸1,3-丙二醇酯，按照制备化合物60所用的化学方法合成化合物62(23％收率)。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.36(s,1H),8.15–7.95(m,3H),7.88–7.71(m,3H),7.41–7.22(m,2H),7.23–7.09(m,4H),7.07–6.97(m,3H),4.54–4.17(m,1H),3.87(s,3H),3.79–3.52(m,1H),3.08–2.54(m,4H),1.84–1.71(m,1H),1.67–1.45(m,2H),1.18–1.03(m,2H)。C34H31N3O4的LR-MS计算值545.23，实测值546.0
8-(4-苄基哌啶-1-羰基)-2-(4-(甲基磺酰基)苯基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(63)
通过用4-(甲烷磺酰基)苯基硼酸代替3-吡啶硼酸1,3-丙二醇酯，按照制备化合物60所用的化学方法合成化合物63(85％收率)。1H NMR(400MHz,DMSO-d6)δ10.05(d,J＝2.1Hz,1H),8.38(s,1H),8.07(d,J＝2.4Hz,1H),7.99–7.94(m,2H),7.92–7.86(m,2H),7.79(dd,J＝8.5,2.4Hz,1H),7.33–7.24(m,2H),7.21–7.11(m,4H),7.06–6.97(m,3H),4.55–4.16(m,1H),3.75–3.53(m,1H),3.24(s,3H),3.05–2.53(m,4H),1.83–1.68(m,1H),1.67–1.45(m,2H),1.18–1.03(m,2H)。C33H31N3O4S的LR-MS计算值565.20，实测值566.1
8-(4-苄基哌啶-1-羰基)-2-(4-(三氟甲氧基)苯基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(64)
通过用4-(三氟甲氧基)苯基硼酸代替3-吡啶硼酸1,3-丙二醇酯，按照制备化合物60所用的化学方法合成化合物12(63％收率)。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.30(s,1H),7.98(d,J＝2.4Hz,1H),7.75–7.64(m,3H),7.49–7.35(m,2H),7.27(dd,J＝8.3,6.4Hz,2H),7.21–7.08(m,4H),7.08–6.93(m,3H),4.58–4.17(m,1H),3.83–3.48(m,1H),3.07–2.53(m,4H),1.83–1.68(m,1H),1.67–1.40(m,2H),1.17–1.05(m,2H)。C33H28F3N3O3的LR-MS计算值571.20，实测值572.2
2-(苯并呋喃-2-基)-8-(4-苄基哌啶-1-羰基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(65)
通过用2-苯并呋喃基硼酸代替3-吡啶硼酸1,3-丙二醇酯，按照制备化合物60所用的化学方法合成化合物65(52％收率)。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.44(s,1H),8.25(d,J＝2.2Hz,1H),7.91(dd,J＝8.4,2.3Hz,1H),7.65–7.56(m,2H),7.38–7.22(m,5H),7.22–7.09(m,4H),7.07–6.94(m,3H),4.61–4.11(m,1H),3.87–3.51(m,1H),3.05–2.53(m,4H),1.84–1.69(m,1H),1.68–1.44(m,2H),1.26–1.00(m,2H)。C34H29N3O3的LR-MS计算值527.22，实测值528.2
8-(4-苄基哌啶-1-羰基)-2-(1H-吡唑-4-基)-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(66)
通过用1H-吡唑-4-硼酸代替3-吡啶硼酸1,3-丙二醇酯，按照制备化合物60所用的化学方法合成化合物66(62％收率)。1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),9.98(s,1H),8.06(s,2H),7.87(d,J＝2.3Hz,2H),7.61(dd,J＝8.3,2.3Hz,1H),7.31–7.25(m,2H),7.21–7.15(m,3H),7.05–6.96(m,4H),4.68–4.17(m,1H),3.89–3.51(m,1H),3.03–2.53(m,4H),1.87–1.70(m,1H),1.67–1.37(m,2H),1.20–1.01(m,2H)。C29H27N5O2的LR-MS计算值477.21，实测值478.2
化合物67的合成。
8-(4-苄基哌啶-1-羰基)-2-乙炔基-5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮(67)
将化合物58(0.100g，0.204mmol)、Pd(PPh3)Cl2(7.1mg，0.01mmol)、CuI(1.9mg，0.01mmol)、三苯膦(10.7mg，0.04mmol)、三甲基甲硅烷基乙炔(31μL，0.224mmol)和二乙胺(0.29mL，2.76mmol)的混合物在二甲基甲酰胺(1mL)中在微波辐射下于120℃加热40分钟。过滤反应混合物，并用二氯甲烷洗涤。在减压下浓缩滤液并且残余物通过在硅胶上快速色谱进行纯化，得到63mg三甲基甲硅烷基保护的中间体。然后将该中间体用在甲醇(3mL)中的碳酸钾(68mg，4mmol)处理，并将反应混合物在室温搅拌1h。将反应混合物过滤，并将滤液减压浓缩，得到残余物，将其通过硅胶快速色谱纯化，得到标题化合物67(46mg，53％，分两个步骤)。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.39(s,1H),7.75(d,J＝2.1Hz,1H),7.42(dd,J＝8.3,2.2Hz,1H),7.33–7.23(m,2H),7.21–7.09(m,3H),7.04–6.65(m,4H),4.50–4.17(m,1H),4.07(s,1H),3.83–3.48(m,1H),3.08–2.53(m,4H),1.87–1.68(m,1H),1.67–1.43(m,2H),1.19–1.01(m,2H)。C28H25N3O2的LR-MS计算值435.19，实测值436.3
实施例2
细胞毒性测定
如前所述，在人PBM、CEM(人淋巴母细胞)和Huh-7细胞中评估了化合物的毒性(参见Schinazi R.F.,Sommadossi J.-P.,Saalmann V.,Cannon D.L.,Xie M.-Y.,Hart G.C.,Smith G.A.&Hahn E.F.Antimicrob.Agents Chemother.1990,34,1061-67)。包括环己酰亚胺作为阳性细胞毒性对照，并且包括未处理的暴露于溶剂的细胞作为阴性对照。使用先前描述的中值有效方法从浓度-反应曲线获得细胞毒性IC50(参见Chou T.-C.&TalalayP.Adv.Enzyme Regul.1984,22,27-55；Belen’kii M.S.&Schinazi R.F.AntiviralRes.1994,25,1-11)。结果示于下表8中：
表1
实施例3
荧光素酶报告基因测定RORα活性
用荧光素酶报告质粒转染Huh-7细胞，该荧光素酶报告质粒含有具有完整野生型(WT)RORα响应元件(RORE)或突变的RORE(mut)的miR-122启动子(从转录起始位点延伸到-900)。转染后一天(24小时)以指定浓度用化合物1处理细胞。处理24小时后测量荧光素酶表达，并将其标准化为由共转染的pRL质粒表达的海肾荧光素酶活性。提供海肾荧光素酶的组成型表达的pRL载体与萤火虫荧光素酶载体结合使用，以共转染细胞。海肾荧光素酶的表达提供了一个内部对照值，可以将实验萤火虫荧光素酶报告基因的表达标准化为该内部对照值。
结果显示，使用WT RORE，化合物1的荧光素酶表达呈剂量依赖性增加。突变RORE会抵消化合物1的活性。如图1所示，这些结果表明了化合物1作为激动剂的RORα活性。
该测定法可用于评估本文所述的其他化合物。在化合物增加萤光素酶表达的情况下，它们是RORα激动剂，而在化合物减少萤光素酶表达的情况下，它们是RORα拮抗剂(或部分激动剂或变构抑制剂)。
实施例4
RORα调节的microRNA的表达。
将Huh-7细胞用1μM化合物1或溶媒(DMSO)处理24小时。通过qRT-PCR分析Huh-7细胞培养基中的分泌的microRNA水平，并针对掺入的(spiked)秀丽隐杆线虫miR-39进行标准化。miR-18和miR-93用作分泌的microRNA的对照，加入化合物1后不受影响。结果示于图2中。
实施例5
Th17群体的调控
从四个健康供体中分离出人外周血单核细胞(PBMC)。进行了四个实验，并在三天的测试内通过流式细胞仪进行了分析。对照组没有药物治疗，第二组用10μM化合物1治疗，第三组用PHA/IL-2刺激未经治疗，第四组用PHA/IL-2刺激并与10μM化合物1孵育。这些结果表明，即使在PHA/IL-2刺激下，化合物1也对CD4+T细胞的总存活力没有影响。此外，在没有PHA/IL-2刺激的情况下，化合物1对Th17群体没有影响。如图3所示，在PHA/IL-2刺激存在下相对于溶媒对照，化合物1减少了PBM细胞中的Th17总种群。
实施例6
C57BL/6小鼠中RORα调节的基因的调控
用7.5mg/kg化合物1或盐水对照腹腔注射健康的C57BL/6小鼠一次。在注射后1、2和7天的时间点处死小鼠。通过qRT-PCR确定每个时间点的miR-122和Gpase 6mRNA水平。将MicroRNA水平标准化为RNU6；将血浆miR-122标准化为掺入的秀丽隐杆线虫miR-39；并且将mRNA水平标准化为HPRT。
这些结果显示在图4A-E中，表明在施用化合物1之后，至多注射后7天，血浆和肝脏中的miR-122水平增加。此外，RORα调节的基因Gpase6在注射化合物1后至多7天被显著上调。
实施例7
高脂肪饮食C57BL/6小鼠的体重减轻归因于RORα调控
给C57BL/6小鼠喂食50％高脂饮食(HFD)，持续四周。对照队列在三周内接受了3次5μg antagomiR-对照的流体动力学尾静脉注射和6次腹腔盐水注射。第二个队列是在三周内流体动力学尾静脉注射了5μg antagomiR-122(抑制miR-122活性的反向互补序列)三次，并腹腔注射盐水六次。第三个队列在3周内每周两次腹腔注射化合物1(7.5mg/kg)，和每周一次腹腔注射antagomiR-对照。最后一个队列在3周内每周两次腹腔注射化合物1(7.5mg/kg)，和每周一次腹腔注射antagomiR-122。
仅注射antagomiR-对照时，小鼠在整个处理过程中从约28g增至30g。用antagomiR-122处理导致体重增加更大，达到最终体重32g。与对照组(缺少化合物1)相比，在实验结束时，用化合物1和antagomiR-对照治疗的组的体重在统计学上较低。化合物1和antagomir-122的共同施用不会降低体重。如图5A-D所示，当用化合物1处理时，miR-122的分泌增强，与antagomir-122的共同施用可将其降低至基线水平。这些结果表明，体重减轻特别是由于化合物1调控的miR-122分泌所致。
实施例8
Sgp130FC小鼠肝甘油三酯和脂质积累的调控。
Sgp130FC小鼠特异性阻断IL-6反式信号转导，而不会影响经典的IL-6信号转导。这些小鼠是非酒精性脂肪性肝炎(NASH)的有用模型，因为它们表现出包括肝肿大、脂肪变性和肝炎在内的疾病症状。使用化合物1(7.5mg/kg)或溶媒对照，每周两次腹腔注射9个月大的Sgp130FC小鼠，持续4周(共8次注射)。4周后处死小鼠，测量肝脏和骨骼肌的甘油三酯水平，并使用H&E染色观察肝脂质积聚。
用化合物1处理可将肝甘油三酯水平显著降低约3倍。如果不进行处理(注射盐水)，则脂质滴在肝脏中积聚，在H&E染色中显示为白色斑点。用化合物1处理明显减少了小鼠中脂质的积聚和液滴的形成。
详细方法
细胞培养。HCC衍生的人类细胞系：Huh7在补充有10％胎牛血清(FCS)、1％青霉素/链霉素的DMEM中培养。
质粒。如前所述(1)，产生了相对于转录起始位点(TSS)跨越-900bp区域的人miR-122启动子片段(质粒PmiR-122-900)。如前所述(2)，通过PCR使用引物P1和P2对启动子区域中的RORα位点进行突变。表2描述了用于产生质粒的所有引物。
萤光素酶测定。对于萤光素酶测定，使用TransIT-LT1(Mirus)转染试剂(MIR2300，Madison，WI)用萤光素酶报告质粒(50ng)和1ng海肾萤光素酶载体(PRL，Promega)共转染在24孔板上生长的细胞。使用双重荧光素酶报告基因检测系统(Promega)评估萤火虫和海肾荧光素酶活性。在Mithras LB 940发光计(Berthold Technologies)上读数，一式三份。
RNA提取和定量实时PCR分析。使用miRNeasy Mini试剂盒(Qiagen，Valencia，CA，USA)并进行了2个小改动，从200μL血浆或培养基样品中分离出总RNA(包括小RNA)。首先，用1ml的Qiazol溶液裂解200μl血浆或培养基。其次，添加50pmol/l的合成单链秀丽隐杆线虫miRNA(cel-miR-39)作为加标(spike-in)对照，以监测提取效率。RNA提取的其他步骤按照制造商的说明进行。用30μl无RNase的水洗脱miRNA。使用TRIzol试剂(Invitrogen，Carlsbad，CA，USA)从细胞或组织中分离出总RNA，包括miRNA。使用Quanta BiosciencesqScriptTM cDNA合成试剂盒(95047-100)合成cDNA，用于mRNA分析，并使用qScriptTMmicroRNA cDNA合成试剂盒(95107-100)合成cDNA，用于进行miRNA分析。分别使用ABI7900HT实时PCR系统和SYBR Green PCR Kit：Quanta Cat.#84018和#84071对miRNA和mRNA进行qRT-PCR。使用2-ΔΔCt方法计算倍数表达(fold expression)和统计学显著性。所有实验均进行三次。
高脂饮食喂养的小鼠。给C57BL/6雄性小鼠喂食50％高脂饮食(Envigo，DIETTD150235)8天。在12h的光/暗周期下，将所有小鼠保持在无病原体的设施中。希伯来大学动物保护与伦理委员会批准了对小鼠的研究。
向小鼠注射化合物1和AntagomiR。对7-8周大的C57BL/6雄性小鼠或9个月大的Sgp130FC雄性小鼠腹腔注射溶于盐水和3％DMSO中的7.5mg/kg化合物1。注射盐水作为对照。给小鼠流体动力学尾静脉注射antagomiR-122或antagomiR-对照(阴性对照)(5μg/小鼠，在1.5ml盐水中)。根据描述实验结果的图例处死小鼠，并将肝脏、白色脂肪和骨骼肌组织冷冻在液氮中或OCT嵌入式冷冻块中，以进行进一步的RNA和组织学分析。从SigmaAldrich获得AntagomiR，请参见表3。
甘油三酯和β-羟基丁酸酯定量。为了确定肝脏和肌肉的脂质含量，将肌肉和肝脏组织(40-80mg)在0.5ml的氯仿：Tris溶液(v/v，1：1)中匀化，将匀化物转移到1ml氯仿：甲醇溶液(v/v，2：1)中，以3000rpm的速度离心10分钟。将有机相与在氯仿中的5％Triton X100混合，干燥并重新溶解在水中。提取脂质后，根据制造商的说明使用甘油三酯定量试剂盒(BioVision)测量样品中的TG浓度。使用商业比色试剂盒(BioVision)直接从血浆样品中测定β-羟基丁酸酯。
表2.质粒构建体的引物。
表3.合成的小RNA。
下标‘m’表示2'-O Me修饰的核苷酸；下标‘s’表示硫代磷酸酯键；‘Chol’表示通过羟脯氨醇键连接的胆固醇。
实施例9
非酒精性脂肪肝疾病(NAFLD)是主要的医疗保健负担，并且与代谢综合征有关，代谢综合征是西方世界上最普遍、最重要的临床流行病。尽管做出了巨大努力，但发展为非酒精性脂肪性肝炎(NASH)的NAFLD目前尚无治疗方法。肝脏miR-122的减少会引起肝脏NASH。我们研究了肝脏中miR-122调节的机制，发现RORα是miR-122的激活剂。选择RORα激活剂化合物1是基于其对增加肝脏、血浆和“远程”组织中的miR-122水平的效应的有益作用。在NASH模型中，我们显示了化合物1可以逆转包括脂肪变性、炎症和纤维化在内的NASH的所有组织学表现。这些作用还与有益的代谢作用和体重减轻有关。因此，RORα激动剂被提议作为治疗、预防和/或逆转NASH的药物。
引言
非酒精性脂肪肝疾病(NAFLD)是全世界最常见的慢性疾病，影响了全球25％以上的人口(Younossi,Hepatology.2016Jul；64(1):73-84)。NAFLD与心血管疾病和糖尿病的增加有关，有30％的患者进展为慢性肝炎，称为非酒精性脂肪性肝炎(NASH)，然后在10-30年内发生纤维化和肝硬化。NASH在15％的病例中也可进展为肝细胞癌(HCC)，并且是全球第二大与癌症相关的死亡的主要原因(Younossi,,J Hepatol.2019Mar；70(3):531-544)。NASH与代谢综合征紧密相关，包括肥胖、糖尿病、高血压、高甘油三酯血症和高密度脂蛋白胆固醇(HDL)含量降低。目前尚无批准的针对NASH和代谢综合征的有效疗法。饮食和遗传是诱导因素，并参与了NASH的发展；但是，我们对两者的影响都在瞬态和边际之间。
尽管NASH是主要的医疗负担，但到目前为止，尚无批准的逆转NASH及其后果的疗法(Konerman，J Hepatol.2018Feb；68(2)：362-375)。最近开发了许多化合物，其中一些已进入II期和III期临床试验。然而，到目前为止，这些都还没有显示出在NASH的所有临床方面的治疗效果，包括脂毒性、炎症、纤维化、胰岛素抵抗和肥胖。
MicroRNA-122(miR-122)与肝脂质代谢有关(Esau,Cell Metab.2006Feb；3(2):87-98)。在患有NASH的人的肝脏中，其水平降低(Cheung,Hepatology.2008Dec；48(6):1810-20)，并且在这些患者的血液中升高。在miR-122基因敲除小鼠中，NASH得以发展(Tsai,J Clin Invest.2012Aug；122(8):2884-97)。脂肪性肝炎在注射了抗miR-122的小鼠中得以发展(Satishchandran,“MicroRNA 122,Regulated by GRLH2,Protects Livers ofMice and Patients From Ethanol-Induced Liver Disease,”Gastroenterology,154(1):238-252(2018))。这些小鼠后来发展成HCC。MiR-122的表达依赖于炎症信号传导，这也说明它从肝脏分泌出来对其他器官有远程的影响。此外，miR-122还受活化肝细胞RORα介导的游离脂肪酸(FFA)的调控。通过FFA-RORα机制可以增加肝细胞中MiR-122的表达，从而通过靶向和降低参与TG生物合成的酶的水平来抑制肝甘油三酯(TG)(Chai,Gastroenterology.2017Nov；153(5):1404-1415)。基于这些观察，采取了一种方法来确定激活RORα是否可以逆转与NASH相关的所有表型。在信息和信念上，以前从未暗示RORα对NASH有直接的有益作用。
开发了一组RORα激动剂，并基于其对miR-122启动子的激活作用选择了一种化合物。这种激活在小鼠模型中对肝脏的脂质毒性产生了有益的肝效应，减轻了肝脏的炎症，并逆转了纤维化。此外，这种RORα激动剂还减少了远端脂肪组织的炎症，改善了胰岛素抵抗，并减轻了肥胖小鼠的体重。
结果
miR-122对高脂饮食(HFD)小鼠脂质代谢的影响
一个最初的问题是，miR-122在高脂饮食(HFD)下引起脂肪毒性的小鼠肝脏中的功能是什么。在人体中，显示出患有NASH的肝脏中的miR-122明显较低(Williams等人，“Newadvances in molecular mechanisms and emerging therapeutic targets inalcoholic liver diseases,”World J Gastroenterol 20(36):12908-33(2014))。在我们之前的报告中，我们显示了miR-122通过降低AGPAT1和DGAT1的酶促活性靶向TG生物合成(Chai,Gastroenterology.2017Nov；153(5):1404-1415)。为了测试降低miR-122在HFD肝脏中的作用，我们通过流体动力学注射向肝脏施用阻断和降解肝细胞中的miR-122的antagomir-122(Krutzfeldt,Nature.2005Dec1；438(7068):685-9)。这也导致了HFD小鼠肝脏中成熟miR-122的减少(Esau,Cell Metab.2006Feb；3(2):87-98)。miR-122前体的水平也有所降低。此外，antagomir-122注射液还显著降低了miR-122的血浆水平。antagomir-122效应在远端组织上也很明显，减少了白色脂肪组织(WAT)中的miR-122。WAT和肌肉中成熟miR-122水平的降低是肝脏细胞中miR-122分泌减少的结果，而不是通过减少非肝脏组织中的miR-122表达而引起的(Chai,Gastroenterology.2017Nov；153(5):1404-1415)。
降低miR-122血浆水平对肌肉组织的远程影响与肌肉TG水平的升高相关。血浆miR-122水平的降低与肝脏脂肪滴和总TG肝含量的增加有关。肝脏miR-122降低的生化作用表现为β氧化、β氧化途径的减少和FFA血浆水平的降低。所有这些都是组织中甘油三酯(TG)存储增加和能量消耗减少的已知迹象。对小鼠体重的总体影响是显而易见的。在HFD时通过antagomir阻断miR-122会导致小鼠体重增加、肝脏重量增加以及肝脏与体重指数增加。在肝脏和全身(远程组织)中减少miR-122的作用是导致肝脏脂质增加、β氧化作用和能量消耗减少，并具有模拟代谢综合征的整体特征的全身作用。
RORα激活
RORα调节miR-122在小鼠中的表达，这是通过FFA介导的(Chai,Gastroenterology,Volume 153,Issue 5,November 2017，1404-1415页)。RFD的水平在HFD时降低，而在用RORα激活剂化合物1激活后增加。但是，与人类新陈代谢和NASH的潜在相关性需要进一步研究。最初对人类NASH数据集进行了研究(参见Arendt,Hepatology,Volume61,Issue 5，1565-1578页(2015)和Starmann,PLoS One.2012；7(10):e46584)(分别为GSE33814和GSE89632)。NASH患者的RORα降低。此外，在这些样品中RORα靶基因减少。在miR-122降低的人类中，miR-122靶基因的表达增加。参与FFA生物合成途径并与脂肪肝相关的基因的表达(Dorn等人，Mol Nutr Food Res.2010Jul；54Suppl 2:S205-13,Knebel,PLoSOne.2012；7(2):e31812)，与RORα呈负相关。随着人类肝脏中RORα的增加，MiR-122靶基因也随之增加。MiR-122靶基因也与RORα表达负相关。FGF21的表达与pre-miR-122正相关。
FGF21是RORα的已知靶标(Wang,J Biol Chem.2010May 21；285(21):15668-73)。最近显示，冷暴露后肝脏中的FGF21上调(Ameka,Sci Rep.2019Jan 24；9(1):630)。尽管不希望受特定理论的束缚，但是据信这可能是由于寒冷时RORα的增加所致。为了评估该假设，将HUH7人HCC细胞用RORα报告系统转染，其中荧光素酶从具有RORα结合位点的miR-122启动子表达。primiR-122和miR-122水平的增加与miR-122靶基因Aldo A和Dgat1的减少有关。根据RORα与其在miR-122启动子中的共有序列的结合，MiR-122的表达对冷敏感。为了确定RORα-miR-122机制对人类是否有意义，还进行了一项人类研究(Hadassah UniversityHospital IRB approval#HMO-0025-18)。在这项研究中，人类正在使用心肺机和全身冷却来进行大血管心血管外科手术。测量了MiR-122的表达，发现降低温度后血浆miR-122显著增加。
这些结果表明，RORα活性的增加和miR-122启动子活性的增加可以增加miR-122对NASH的肝有益作用。另外，该作用可能是全身性地产生治疗作用，例如改善胰岛素抵抗和减少脂肪组织和体重。为此，产生了一组RORα激动剂。
RORα由以下组成：与共激活蛋白相互作用的N末端激活功能1(AF-1)，随后是包含两个锌指基序的DNA结合域、柔性铰链区和包含激素反应性激活功能2(AF-2)的C末端配体结合域(LBD)。激动剂与RORα-LBD的结合可以诱导构象变化，使共激活蛋白能够与AF-2结合。与RORα-LBD配合解决问题的最有效的激动剂是硫酸胆固醇(PDBID 1S0X)。通过高通量虚拟筛选靶向该晶体结构的该配体结合口袋，以鉴定新的RORα激动剂。使用SchrodingerMaestro Glide HTVS工作流程评估了300,000种类药性化合物的专有文库的结合能力。使用Prime MMGBSA(允许
的柔性)进一步对前200种化合物进行了评分。目视检查前100种化合物，并在miR-122启动子区域使用荧光素酶测定法选择了十二种进行评估。
RORα的肝脏和全身作用通过miR-122介导
为了确定RORα代谢和生化作用是否通过miR-122介导，进行了以下实验。化合物1的激活作用是通过使miR-122启动子中的该位点突变而经过RORαDNA与miR-122启动子的结合/激活来实现的。将HuH7细胞暴露于化合物1 16h后，miR-122的细胞水平未发生变化，但培养基中分泌了显著的miR-122(通过LDH释放测定，对细胞无明显毒性，数据未显示))。但是，将化合物1对小鼠施用数周后，miR-122水平在肝脏和血浆中均升高。这与Pre-miR-122和Pri-miR-122二者的肝前体水平增加，以及miR-122的已知靶标AldoA的降低，以及G6Pase(一种已知的RORα靶基因)的升高有关(Chauvet,PLoS One.2011；6(7):e22545)。MiR-122可到达远端组织。为了评估化合物1对这种miR-122远程效应的作用，在心肌组织中测量了miR-122，其显示出成熟的miR-122水平升高，而三个miR-122靶基因却相应下调。施用化合物1后，还鉴定了其他器官如WAT和肌肉中的成熟miR-122(未检测到肌肉组织中pri-miR-122的水平，这表明肌肉中的成熟miR-122不是由miR-122启动子表达的)。
为了确定miR-122和化合物1的作用机理是否在同一途径上对齐，设计了一个实验，将两种分子一起以及分别施用。在这项研究中，给小鼠喂食50％的HFD，并在动物饮食后4周开始治疗，以在处理前建立NASH。4周后开始治疗(由于antagomiR的半衰期长，每周一次给予antagomiR，并且由于RS的血浆t1/2为2.7小时，每周给予两次RS)，并持续3周。从第3周开始对小鼠称重，并在一周后开始治疗。对照小鼠(每周一次给予antagomiR-对照，每周两次给予稀释于盐水中的DMSO)体重稳定增加。施用antagomir-122的小鼠体重增加最大。那些用RORα激动剂化合物1处理过的动物，体重稳定下降并减轻了体重。施用了antagomir-122和化合物1二者的小鼠，其体重完全恢复到对照动物的体重。这一现象表明，miR-122和化合物1可能彼此拮抗。此外，还表明体重的减少不是由于毒性作用。在实验停止时，经antagomiR-122处理的动物体重显著增加，表明肝脏中miR-122的减少与全身作用有关，而化合物1的施用在实验结束时也显著减轻了体重。肝脏重量因此减少。进一步分析肝脏以评估脂质毒性。在经化合物1处理的小鼠中，肝脂质滴和TG含量降低，在注射了antatagomiR-122的小鼠中，这种降低被完全消除，表明化合物1对脂肪变性的有益作用是由miR-122活性介导的。还测量了能量消耗的替代指标β-羟基丁酸酯。能量消耗的减少与miR-122的减少有关，并且在用化合物1处理后能量消耗增加。
这些作用与施用antagomiR-122后肝脏和血浆中miR-122的减少以及施用化合物1时肝脏和血浆二者中miR-122的增加有关。MiR-122的增加也对其靶基因(包括Agpat1、Dgat1和FGF21)有影响。肝antagomiR-122和化合物1也对肌肉产生了与肝脏相似模式的作用，可能是通过miR-122分泌作用。这导致对肌肉TG含量的影响，其中antagomiR-122增加了肌肉中TG含量，而化合物1降低了肌肉中TG含量，可能是通过肝脏衍生的分泌的miR-122引起的。肝脏中FGF21信息的水平与pri-miR-122的水平相关，表明存在共同调节作用。这些观察结果加强了我们的假设，即通过antagomiR-122降低肝脏的miR-122的水平或通过化合物1升高肝脏的miR-122的水平来控制miR-122水平具有肝/中枢和远端/外周的作用。化合物1的总体作用最终导致与脂毒性降低相关的重量的显著降低。
通过激活RORα-miR-122-甘油三酯循环(circuitry)来提高抗脂毒性并改善代谢
作用
在证明化合物1是具有有益的生化作用的临床相关miR-122激活剂后，接下来的研究旨在确定其对脂毒性和代谢作用的影响。对患有确定的NASH的小鼠施用化合物1。激活剂增加了小鼠肝脏和血浆中的miR-122水平。RORα激活剂/激动剂化合物1化合物的施用导致miR-122前体以及RORα靶标的增加。这些结果表明，激活剂在模型中确实起作用。在NASH模型中，化合物1显著降低了接受HFD的动物的体重。通过观察单只动物的作用并通过计算动物身体：肝脏重量，这种作用也很明显。RORα激活剂逆转了小鼠肝脏的脂毒性作用及其TG含量。化合物1诱导miR-122的产生和从肝细胞的分泌，也具有减轻WAT炎症的作用。这些有益的组织学和生化作用不仅导致体重减轻，而且与胰岛素耐受性的改善有关。
用化合物1激活RORα-miR-122-甘油三酯循环的抗炎和抗纤维化作用
一旦观察到RORα激活剂化合物1在肝脏和远端组织中具有显著的抗脂毒性，减轻了体重并具有有益的代谢特性，就可以确定化合物1对肝脏炎症和纤维化的作用。在小鼠动脉粥样化饮食模型中评估了化合物1对肝脏炎症和纤维化的作用(Anavi,LabInvest.2015Aug；95(8):914-24)。在饮食的第3周出现肝炎症和纤维化之后，动物开始接受化合物1。在另外3.5周后，其中动物每周接受3次化合物1，评估了动物的许多终点事件。化合物1显著改善了肝酶。证实了在施用化合物1后，组织和血浆中的成熟miR-122均增加。化合物1显著改善了肝脏炎症。炎症的这种改善与肝纤维化的显著减少有关，这可通过两种方法进行评估，即Masson三色染色和αSMA染色。如这些小鼠肝脏的CD34染色所示，化合物1对肝血管没有作用(数据未显示)。RORα激活剂化合物1的作用对纤维化驱动基因也很明显。
讨论
激活RORα具有巨大的抗NASH有益作用。这些作用既涉及与NASH相关的肝脏病理，也涉及肝脏的周围组织。RORα对NASH和代谢综合征相关病症的有益作用是通过成熟的miR-122介导的，尽管其他RORα活性可能会有助于这些有益作用。miR-122的作用是通过靶向TG生物合成中的中心酶的表达来抑制肝脂质毒性，脂肪肝的第一击点(hit)(Engin,Adv ExpMed Biol.2017；960:443-467)。根据证据，表明RORα激活了miR-122的表达并增加其向血浆中的分泌，到达WAT、肌肉和心肌，加快其远程作用，我们提出RORα激活的作用在肝脏和全身都有。
为了控制RORα的激活并增强其潜在的有益作用，开发了一种筛选系统来鉴定增强RORα对miR-122表达的活性并具有较好的抗NASH作用的化合物。我们已经鉴定出一种在NASH中具有潜在治疗作用的化合物(化合物1)。有趣的是，增加miR-122表达和分泌的化合物1显示出显著的代谢作用，包括减少脂肪肝、抑制与肝脂毒性有关的肝脏炎症、逆转肝纤维化、改善胰岛素抵抗和减轻体重。
NASH是世界范围内对治疗的高度优先未满足需求。如今，NASH还没有一种获批的药物。针对与代谢综合征和NASH相关的特定疾病开了许多药物处方(Wattacheril,AnnuRev Pharmacol Toxicol.2018Jan 6；58:649-662)。然而，除了建议他们接受特定饮食例如在一定程度上改善NAFLD的地中海饮食之外，NASH患者仍然没有治疗选择(Marchesini,Hepatology.2016Jun；63(6):2032-43)。许多化合物正在药物开发线路中，一些化合物显示出有趣的前景(Friedman,Nat Med.2018Jul；24(7):908-922)，还有一些未能满足重要的终点事件(Loomba,Gastroenterology.2019Jan；156(1):88-95)。
以前的许多报告以及我们的报告都指出了“劫持”的可能性，这是miR-122在肝脏中作为抗脂毒性效应物的机制作用。我们决定研究miR-122的潜在治疗作用的原因之一，除了它是一种“天然”效应物外，还因为它具有“miR激素”作用的事实。与许多其他microRNA一样，MiR-122在一个组织中产生，在肝脏中具有抗血脂作用并到达远端组织。已经表明，从肝脏产生和分泌miR-122并到达肾脏，在那里它靶向促红细胞生成素，降低其蛋白质水平并引起贫血(Rivkin,M.等人.Inflammation-Induced Expression and Secretion ofMicroRNA 122Leads to Reduced Blood Levels of Kidney-derived Erythropoietinand Anemia.Gastroenterology(2016))。
在肝脏中产生miR-122的机制很强大。每个肝细胞存储250,000个拷贝的miR-122和miR-122*(Simerzin,Hepatology.2016Nov；64(5):1623-1636)。miR-122的有效远程活性取决于miR-122的高产量和分泌，以产生高血浆水平。如此高的生产率表明miR-122可以转译为有效的治疗化合物。但是，与其开发一种系统，其中合成合成型miR-122(mimic-miR-122)、将其制成药物并注射到NASH患者，持续数年，将优选的是开发一种可诱导肝内源性miR-122的表达，并且可以每天给予患者的小药物。MiR-122也通过TNFα信号传导表达和分泌。但是，在NASH的临床环境中，注射TNFα没有意义。MiR-122还具有与NASH相关的其他治疗特性。miR-122，既有miR-122-5p又有miR-3p(miR-122*)，具有肿瘤抑制作用Simerzin,Hepatology.2016Nov；64(5):1623-1636(Luna等人,Mol Cell.2017Aug 3；67(3):400-410)、(Sun等人,Cancer Cell.2016Nov 14；30(5):723-736)。
在NASH患者中，这种积极的“副作用”在临床上很重要，这增加了将基于promiR-122的化合物开发成为药物的动机(Bandiera,J Hepatol.2015Feb；62(2):448-57)。最近提出了RORα在NASH预防中的潜在有益作用。NASH在RORα基因敲除(KO)小鼠中加重(Kim等人，Sci Rep.2017Nov 22；7(1):16041)。通过以RORα依赖性方式增加巨噬细胞中Maresin 1(MaR1)的产生，将肝脏巨噬细胞转化为M2抗炎表型(Han等人，J Clin Invest.2019Mar 11；130:1684-1698)。然而，在这些报道中，仅炎性NASH表型被预防并且未被治疗。
该报告中显示的数据表明，RORα激活可增加肝脏和其他器官(包括脂肪组织)中的miR-122，具有显著的抗NASH活性。因此，RORα活化剂被提议作为有前景的待开发化合物，并评估其对患者NASH的临床有益作用。
材料和方法
细胞培养
在补充有10％胎牛血清(FCS)、1％青霉素/链霉素的DMEM中培养人肝癌细胞系-Huh7(Thermo Scientific,Waltham,MA,USA)。将细胞在37℃下在含有5％CO2的潮湿气氛中培养，除了如本文所示将细胞置于32℃的实验以外。
RNA提取和定量的实时RT-PCR
使用进行了2个小改动的miRNeasy微型试剂盒(Qiagen,Valencia,CA,USA)，从200μL血浆或培养基样品分离出总RNA(包括小RNA)。首先，用1ml的Qiazol溶液裂解200μl血浆或培养基。其次，添加50pmol/l的合成单链秀丽隐杆线虫miRNA(cel-miR-39)作为加标对照，以监测提取效率。RNA提取的其他步骤按照制造商的说明进行。用30μl无RNase的水洗脱miRNA。使用TRIzol试剂(Invitrogen，Carlsbad，CA，USA)从细胞或组织中分离出总RNA，包括miRNA。使用Quanta Biosciences qScriptTM cDNA合成试剂盒(95047-100)合成cDNA，用于mRNA分析，并使用qScriptTM microRNA cDNA合成试剂盒(95107-100)合成cDNA，用于进行miRNA分析。分别使用ABI 7900HT实时PCR系统和SYBR Green PCR Kit：Quanta Cat.#84018和#84071对miRNA和mRNA进行qRT-PCR。使用2-ΔΔCt方法计算倍数表达和统计学显著性。所有实验均进行三次。用于qRT-PCR的引物示于表1。
质粒
如前所述1,2，产生了相对于转录起始位点(TSS)跨越-900bp区域和使RORα结合位点突变的人miR-122启动子片段(分别为质粒PmiR-122-900和PmiR-122-RORαmut)。
转染
对于萤光素酶测定，使用脂质体LTX(Invitrogen)转染试剂将萤光素酶报告质粒(50ng)和1ng海肾萤光素酶载体(PRL，Promega)共转染在24孔板上生长的细胞。对于所有实验，使用无血清培养基进行转染(Opti-MEM；Cat#31985070；Thermo Scientific)。
萤光素酶活性测定
转染后，将细胞用被动裂解缓冲液(Cat#E1941；Promega)裂解，在室温下振摇20分钟，然后转移到合适的96孔板中。使用双重荧光素酶报告基因测定系统(Cat#E1910；Promega)在照度计Mithras 2000(Centro XZ,LB960,Berthold Technologies,BadWildbad,Germany)上评估萤火虫和海肾荧光素酶的活性。将所述荧光素酶活性标准化为海肾荧光素酶活性。三次读数。
RORα激动剂治疗
通过溶解在DMSO(1mg/ml)中来制备商业RORα激动剂SR1078(Cayman Chemical)和RORα化合物储备液。将Huh7细胞用5μM SR1078或1μM的所有其他受测试化合物处理过夜。单独使用DMSO(0.2％)作为对照。将RORα激动剂化合物1溶于盐水和至多5％DMSO中，并根据文字剂量经腹腔注射给小鼠。定量化甘油三酯、游离脂肪酸和β-羟基丁酸酯。
为了确定肝脏和肌肉的脂质含量，将肌肉和肝脏组织(40-80mg)在0.5ml的氯仿：Tris溶液(v/v，1：1)中匀化，将匀化物转移到1ml氯仿：甲醇溶液(v/v，2：1)中，以3000g(在-2℃)速度离心10分钟(Heraeus Megafuge 16R离心机)。将有机相与在氯仿中的5％TritonX100混合，干燥并重新溶解在水中。提取脂质后，根据制造商的说明使用甘油三酯定量试剂盒(BioVision)测量样品中的甘油三酯(TG)浓度。使用商业比色试剂盒(BioVision)直接从血浆样品中测定血浆游离脂肪酸和β-羟基丁酸酯。
动物研究
7-8周大的雄性C57BL/6小鼠购自Harlan Laboratories(以色列耶路撒冷)。在12h的光/暗周期下，将所有小鼠保持在无病原体的设施中。根据由美国国家科学院编写并由美国国立卫生研究院出版的“实验动物的护理和使用指南”中概述的标准对小鼠进行处理。希伯来大学动物保护与伦理委员会批准了对小鼠的研究；伦理编号MD-15-14423-3。
对高脂饮食(HFD)喂养的小鼠的AntagomiR-122治疗
给7-8周大的C57BL/6小鼠喂食饲料或50％HFD(由50％脂肪、20％蔗糖、10％果糖、1.25％Chol(Envigo，TD.150235)组成)，持续4周。在通过antagomiR抑制miR-122的实验中，每周一次给小鼠流体动力学尾静脉注射antagomiR-122或antagomiR-对照(5μg/小鼠，在1.5mL盐水中)，持续4周，并且仍喂养HFD或饲料。注射4周后，处死小鼠，将肝脏、白色脂肪和骨骼肌组织在液氮中或在最佳切割温度下嵌入的冷冻块中冷冻，以进行进一步的RNA和组织学分析。AntagomiR购自Sigma-Aldrich(密苏里州圣路易斯)；参见表2。
对喂养HFD或致动脉粥样硬化饮食的小鼠的化合物1和AntoagomiR-122治疗
将7-8周大的雄性C57BL/6J小鼠随机饲养在标准笼中，并喂以HFD或致动脉粥样化饮食(由1％的Chol和0.5％的胆酸组成，另见表3)。在实验期间，所有小鼠均可自由饮水。在喂养期间，每3天监测一次体重。在HFD实验中，在4或6周后，将所得肥胖小鼠用antagomiR-122(5μg/小鼠，每周一次，持续3周)治疗，或腹腔注射化合物1(RORα激动剂，每周两次，每次7.5mg/kg，持续3周；或每周3次，每次15mg/kg，持续3周)。肥胖对照(HFD)组仅给予生理盐水、DMSO和antagomiR对照。处理3周后，处死小鼠，取出肝脏用于RNA-seq分析。将肝脏、白色脂肪和骨骼肌组织在液氮中或在最佳切割温度下嵌入的冷冻块中冷冻，以进行进一步的RNA和组织学分析。在致动脉粥样化饮食实验中，饮食3周后用15mg/kg化合物1处理小鼠。治疗3.5周后，处死小鼠，将肝脏在液氮中或在最佳切割温度下嵌入的冷冻块体中冷冻。从动脉粥样化饮食喂养的小鼠中收集血浆，并保存在-20℃中，以使用
分析仪和测试条(Roche)进行ALT和AST分析。
多参数代谢评估
通过使用Promethion高清晰度行为表型系统(美国内华达州拉斯维加斯的SableInstruments公司)测量小鼠的代谢和活动状况，该系统是一种多参数评估，其中包含在一个最大限度地减少压力的常规家用笼中的用于开路间接量热法、进食、进水、活动、跑轮和体重测量的子系统。使用MetaScreen软件2.2.18.0版进行数据采集和仪器控制，并使用ExpeData 1.8.4版使用详细描述数据转换各个方面的分析脚本对获得的原始数据进行处理。将C57BL/6小鼠用HFD喂养6周，然后用15mg/kg化合物1处理，每周3次，持续2周，接着将其放置在代谢室中，自由进食和饮水，并接受标准12h暗/12h暗周期，其中包括24h的适应期和接着48h的采样持续时间。通过使用GA-3气体分析仪(美国内华达州拉斯维加斯的SableSystems公司)使用拉模式负压系统测量呼吸气体。由FR-8(美国内华达州拉斯维加斯的Sable Systems公司)测量和控制气流，设定流速为2000mL/min。连续测量水蒸气，并通过数学补偿其对O2和CO2的稀释作用。通过ANCOVA分析计算有效质量。呼吸商(RQ)计算为VCO2/VO2之比。总能量消耗(TEE)计算为VO2 x(3.815+1.232x RQ)，归一化为有效体重，并表示为kcal/h/kgeff.质量。脂肪氧化(FO)和碳水化合物氧化(CHO)计算为：FO＝1.69x VO2–1.69xVCO2和CHO＝4.57x VCO2–3.23x VO2并表示为g/d/kgeff.质量。使用XYZ光束阵列并以0.25cm的光束间距监控动态活动和位置，并同时收集量热数据。
油红O染色
将肝组织包埋在最佳切割温度凝胶中，并切成10μm冷冻切片。对于油红O染色，准备了油红O(Sigma-Aldrich)(1g/10mL在丙二醇中)的储备溶液、过滤并避光保护。将冷冻切片浸入福尔马林中，用油红O染色15分钟，然后用苏木精复染30秒钟。
人体血液样本和肝素消除
为了测量miR-122，从使用心肺机和全身冷却进行大血管心血管手术的患者采集血液样本，进行了FFA和人FGF21(abcam)分析。这是在Hadassah医院IRB委员会批准编号0025-18-HMO的批准下进行的。所有受试者均获得使用生物材料进行研究的知情同意和许可。2号管表示手术期间为患者降温之前的时间，3号管表示手术期间体温最低的时间。根据先前描述的方案3,4，从患者血浆样品中分离的RNA溶液中去除肝素，简短地，将5μL在水中的RNA样品与5μL的肝素酶工作溶液(0.085IU/mL的肝素I(Sigma-Aldrich；产品目录号H2519)、2000单位/mL的RiboLock RNase抑制剂(Life Technologies；产品目录号EO0381)、10mmol/L Tris HCl pH 7.5、2mmol/L CaCl2、25mmol/L NaCl混合物并在25℃保持3小时。反应后，样品直接用作RNA模板用于逆转录反应。
胰岛素耐受性测试
在4个月大时，在HFD喂食9周后，在用DMSO注射剂施用化合物1或盐水后，对禁食的C57BL/6雄性小鼠进行胰岛素耐受性测试。小鼠接受了腹腔注射剂量为0.88单位/千克的人胰岛素(Actrapid)，然后每20分钟检查一次葡萄糖。胰岛素注射后0、20、40、60、80和100分钟测量葡萄糖水平。使用血糖仪(Accu-Chek)和试纸(Accu-Chek)在指定的时间点对尾巴剪短后尾部的血液进行葡萄糖测量。
组织的组织学和免疫组织化学
将肝脏和脂肪样品置于4％的甲醛缓冲液中放置24小时，然后置于80％的乙醇中，然后包埋在石蜡块中。将肝脏和脂肪组织切成5毫米的切片，用二甲苯脱蜡并通过分级乙醇进行水合。对于H&E染色，组织切片用苏木精(Emmonya Biotech Ltd.)和曙红(Leica，Surgipath)染色。肝巨噬细胞先用大鼠抗小鼠F4/80抗原(Serotec)染色，再用抗大鼠HRP(Histofine)染色，并用DAB试剂盒(Zymed)显影。对肝脏切片进行Masson三色(Sigma)的染色。肝CD3+T细胞先用大鼠抗人CD3抗体(Bio-Rad)染色，再用抗大鼠HRP(Histofine)染色，并用AEC(Invitrogen)显影。α-SMA阳性细胞先使用小鼠抗人类平滑肌肌动蛋白抗体(Dako)染色，然后使用抗小鼠HRP(Dako)染色并用DAB显影。通过ImageJ软件在5-10个随机视野中计算每个高倍视野正染区域的百分比。
统计分析
使用Excel软件包(Microsoft,Redmond,WA)或GraphPad Prism6(GraphPadSoftware Inc.,La Jolla,CA)，对数据进行统计分析。使用双尾学生t检验以及Pearson和Spearman相关系数确定两组之间的差异。数据以平均值±SD给出，并显示为所有实验的误差条。差异在P＜0.05时被认为是显著的。报告的数据是从至少3个生物学重复中获得的。
表1.用于实时PCR的引物
表2.用于本研究的antagomiR序列。所有寡核苷酸均由IDT(IDT，Coralville，IA，USA)合成。反义寡核苷酸的化学修饰：下标‘m’表示2'-O Me修饰的核苷酸；下标‘s’表示硫代磷酸酯键；‘Chol’表示通过羟脯氨醇键连接的胆固醇。
表3.正常饮食和致动脉粥样硬化饮食组合物。
参考文献：
1.Chai,C.等人Metabolic Circuit Involving Free Fatty Acids,microRNA122,and Triglyceride Synthesis in Liver and Muscle Tissues.Gastroenterology153,1404–1415(2017).
2.Rivkin,M.等人Inflammation-Induced Expression and Secretion ofMicroRNA 122Leads to Reduced Blood Levels of Kidney-derived Erythropoietinand Anemia.Gastroenterology(2016).doi:10.1053/j.gastro.2016.07.031
3.Kondratov,K.等人Heparinase treatment of heparin-contaminated plasmafrom coronary artery bypass grafting patients enables reliable quantificationof microRNAs.Biomol.Detect.Quantif.8,9–14(2016).
4.Izraeli,S.,Pfleiderer,C.&Lion,T.Detection of gene expression by PCRamplification of RNA derived from frozen heparinized whole blood.NucleicAcids Res.19,6051(1991).
实施例10
证明化合物1在NASH小鼠模型中起有效的RORα激动剂的作用，并改善了甘油三酯的水平。
实验设计：用高脂饮食(HFD)喂养C57BL/6小鼠持续6周，每周3次注射15mg/kg化合物1(或盐水+DMSO)，注射3周(n＝6)。
图7A和图7B分别示出了在用化合物1或盐水处理的小鼠中从血浆和肝脏提取的miR-122的qRT-PCR分析的结果。图7C显示了从小鼠肝脏提取的RORα靶基因pri-miR-122和pre-miR-122mRNA的qRT-PCR分析。图7D是示出了肝脏甘油三酯(TG)水平的定量的图。
用化合物1处理诱导miR-122和前体在血浆和肝脏中的表达和分泌。另外，用化合物1处理显著诱导了RORα调节的基因FGF21和Gpase6的表达。与未处理的HFD小鼠相比，用化合物1处理可使甘油三酯水平降低5倍。
实施例11
RORα激动剂化合物1改善NASH小鼠模型的体重和肝脂质积聚。
实验设计：用HFD喂养C57BL/6小鼠持续6周，每周3次注射15mg/kg化合物1(或盐水+DMSO)，注射3周(n＝6)。
图8A显示实验期间测量的体重。图8B显示了肝脏的H&E染色，图8C显示实验结束时测得的肝脏/体重比(％)。对照小鼠(每周一次施用antagomiR-对照，每周两次施用在盐水中稀释的DMSO)体重稳定增加。施用antagomir-122的小鼠体重增加最大。那些用RORα激动剂化合物1处理过的动物，体重稳定下降并减轻了体重。给小鼠施用antagomir-122和化合物1二者，其体重完全恢复到对照动物的体重。这一现象表明，miR-122和化合物1可能彼此拮抗。此外，还表明重量的减少不是由于毒性作用。在实验停止时，经antagomiR-122处理的动物体重显著增加，表明肝脏中miR-122的减少与全身作用有关，而化合物1的施用在实验结束时显著减轻了体重。进一步分析肝脏以评估脂质毒性。在经化合物1处理的小鼠中，肝脂质滴降低，而在注射了antatagomiR-122的小鼠中，这种降低被完全抵消，表明化合物1对脂肪变性的有益作用是由miR-122活性介导的。因此，与未处理的组相比，处理组的肝脏/体重比降低。
实施例12
RORα激动剂化合物1改善NASH小鼠模型的代谢输出。
实验设计：用HFD喂养C57BL/6小鼠持续6周，每周3次注射15mg/kg化合物1(或盐水+DMSO)，注射3周(n＝8)。代谢笼：在化合物1或盐水处理2周后，通过Promethion高清晰度行为表型分析系统(Sable Instruments，Inc.)在24小时内监测小鼠。
结果示于图9A-E中，其是显示当向C57BL/6小鼠施用化合物1或对照(盐水+DMSO)时，小鼠模型在24小时内的代谢输出的变化的图。图9A比较了溶媒vs化合物1处理的小鼠中的体积O2(1/d/kg0.75)。图9B比较了溶媒vs化合物1处理的小鼠中的体积CO2(1/d/kg0.75)。图9C比较了溶媒vs化合物1处理的小鼠中的总能量消耗(Kcal/h/kg0.75)。图9D比较了溶媒vs化合物1处理的小鼠中的脂肪氧化(g/d/kg0.75)。图9E比较了溶媒vs化合物1处理的小鼠中的碳水化合物氧化(g/d/kg0.75)。
注意与盐水(溶媒)处理的动物相比，化合物1处理的小鼠中总能量消耗(TEE；J)增加；且脂肪氧化(K)增加。有效质量由0.75的幂计算。数据是每组8只小鼠的平均值±SEM。
实施例13
RORα激动剂化合物1恢复NASH小鼠模型的胰岛素敏感性。
实验设计：用HFD喂养C57BL/6小鼠持续6周，每周3次注射15mg/kg化合物1(或盐水+DMSO)，注射3周(n＝6)。用HFD喂养的经化合物1处理的小鼠vs用HFD喂养的经盐水处理的小鼠和用正常饮食喂养的小鼠(对照ND)在胰岛素耐受性测试(ITT)期间的全血葡萄糖水平；分钟表示注射胰岛素后的时间。n.s.＝不显著。
结果示于图10中。在正常饮食喂食的小鼠中，血糖水平在55分钟后降至约55％，并在100分钟后恢复至60％。HFD队列的血糖水平最初下降至约65％，并在100分钟后反弹至80％。在注射后45分钟后，经化合物1处理的队列显示出血糖初始降低至～55％，然后在100分钟后恢复至70％。这些结果表明，与未经处理的队列相比，化合物1提高了胰岛素敏感性。
实施例14
RORα激动剂化合物1可改善纤维化饮食小鼠模型中肝损伤和纤维化的标志物。
实验设计：C57BL/6小鼠用致动脉粥样化的饮食(诱发纤维化)喂养3周，且每周3次注射15mg/kg化合物1(或盐水+DMSO)，持续3.5周(n＝8)。
结果示于图11A-D。对于未经治疗(灰色柱)和经治疗(黑色柱)的队列，从A)血浆和B)肝脏中提取的miR-122的qRT-PCR分析。血浆和肝脏中的miR-93和miR-18分别用作阴性对照。C)实验结束时测得的ALT和AST血浆水平。D)从小鼠肝脏提取的纤维化中涉及的基因和RORα靶基因(Fgf21)的mRNA的qRT-PCR分析。将血浆中的microRNA水平标准化至掺入的秀丽隐杆线虫miR-39；将组织中的microRNA水平标准化至RNU6。mRNA水平标准化至HPRT。数据以误差条＝SD表示。*P<.05，**P<.01。***P<.001，****P<0.0001。
当观察到RORα激活剂化合物1在肝脏和远端组织中具有显著的抗脂毒性，减轻了体重并具有有益的代谢特性时，我们受鼓励确定化合物1对肝脏炎症和纤维化的作用。已经评估了化合物1对小鼠动脉粥样硬化饮食模型中肝脏炎症和纤维化的作用。在饮食的第3周出现肝炎症和纤维化之后，动物开始接受化合物1。在另外3.5周后，其中动物每周接受3次化合物1，评估了动物的许多终点事件。我们确认了在施用化合物1后，成熟的miR-122在组织和血浆中均增加。用化合物1进行的处理，除了减少炎症的生物标志物(Tgfb2和TgfbR2)和纤维化的生物标志物(Acta1、Col1A1和Col3A1)外，还显著改善了肝损伤的生物标志物AST和ALT。
实施例15
RORα激动剂化合物1可改善纤维化饮食小鼠模型中肝炎性特征。
实验设计：C57BL/6小鼠用致动脉粥样化的饮食(诱发纤维化)喂养3周，且每周3次注射15mg/kg化合物1(或盐水+DMSO)，持续3.5周(n＝8)。图12A显示了从经盐水或经化合物1处理的小鼠获取的H&E、CD3和F4/80染色的肝脏的代表性显微照片，其中比例尺代表10μm。图12B中示出的图显示使用ImageJ对阳性染色的F4/80区域进行定量。
经化合物1处理的小鼠，通过H&E染色显示免疫浸润减少，通过CD3染色显示T细胞密度降低，通过F4/80染色显示髓样浸润水平降低。这些结果证明化合物1表现出抗炎作用。
实施例16
RORα激动剂化合物1降低纤维化饮食小鼠模型中肝纤维化。
实验设计：C57BL/6小鼠用致动脉粥样化的饮食(诱发纤维化)喂养3周，且每周3次注射15mg/kg化合物1(或盐水+DMSO)，持续3.5周(n＝8)。结果示于图13A-D。
图13A和C是取自经盐水或经化合物1处理的小鼠的Masson三色(M.T.)染色和α-SMA染色的肝脏的代表性显微照片，其中比例尺代表10μm。图13B和D是示出使用ImageJ对阳性染色区域进行定量的图。
利用两种染色评价化合物1对肝纤维化的作用(Masson三色和α-SMA)。使用两种染色方法，未处理的队列显示出较大的阳性面积，而用化合物1处理使纤维化区域显著降低了5倍(M.T)和7倍(α-SMA)。这些观察结果强烈支持化合物1在该小鼠模型中表现出抗纤维化活性。
本发明不限于本文所述的具体实施方案的范围。实际上，除了所描述的那些之外，本发明的各种修改对于本领域技术人员来说从前面的描述和附图中是显而易见的。这些修改旨在落入所附权利要求的范围内。
本文引用了各种出版物，其公开内容通过引用整体并入。
Claims (45)
1.式(A)的化合物：
或其药学上可接受的盐或前药，其中：
其中X和Z之一选自由以下组成的组：-NH-、-N(NH2)-、-NH(OH)-、N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-、-O-、-CH2-、-CH(C1-10烷基)-、C(C1-10烷基)2-、-CH(C3-10环烷基)-、-CH(C2-10烯基、-CH(C2-10炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O-C1-10烷基)-、-CH(NH2)-、-CH(NH-C1-10烷基)-和-CH(C(O)NH2)-，
而X和Z中的另一个选自由以下组成的组：-C(O)-、-SO2-、-N(C(O)-、-CH2-、-CH(C1-10烷基)-、C(C1-10烷基)2-、-CH(C3-10环烷基)-、-CH(C2-10烯基、-CH(C2-10炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O烷基)-、-CH(NH2)-、-CH(NHC1-10烷基)-和-CH(C(O)NH2)-，
Y选自由以下组成的组：-NH、-N(NH2)-、-NH(OH)-、N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-、或-N(杂芳基)-、-O-、-CH2-、-CH(C1-10烷基)-、-CH(C3-10环烷基)-、-CH(C2-10烯基、-CH(C2-10炔基)-、-CH(芳基)-、-CH(杂芳基)-、-C(C1-10烷基)2-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O-C1-10烷基)-、-C(O)-、-SO2-、-N(C(O)-C1-10烷基)-、-N(C(O)O-C1-10烷基)-、-CH(NH2)-、-CH(NH-C1-10烷基)-和-CH(C(O)NH2)-，
A和B独立地是苯基、含有一个、两个或三个氮、氧或硫原子的五元杂芳族环或含有一个、两个或三个氮原子的六元杂芳族环；
u和v独立地为0、1、2、3或4；条件是u和v中的至少一个为1、2、3或4；
每个R1和R2独立地为R3、OH、OR3、SR3、S(O)R3、SO2R3、C(O)R3、C(O)OR3、OC(O)R3、OC(O)OR3、NH2、NHR3、NHC(O)R3、NR3C(O)R3、NHS(O)2R3、NR3S(O)2R3、NHC(O)OR3、NR3C(O)OR3、NHC(O)NH2、NHC(O)NHR3、NHC(O)N(R3)2、NR3C(O)N(R3)2、C(O)NH2、C(O)NHR3、C(O)N(R3)2、C(O)NHOH、C(O)NHOR3、C(O)NHSO2R3、C(O)NR3SO2R3、SO2NH2、SO2NHR3、SO2N(R3)2、COOH、C(O)H、C(N)NH2、C(N)NHR3、C(N)N(R3)2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、-CH2-膦酸酯、-CH2O-磷酸酯、CH2P(O)(OH)2、CH2P(O)(OR3)2、CH2P(O)(OR3)(NR3)、CH2P(O)(NR3)2、CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)或CH2-环Sal单磷酸酯前药，
其中术语磷酸酯包括单磷酸酯、二磷酸酯、三磷酸酯和稳定化的磷酸酯前药，术语膦酸酯包括与磷酸酯前药中存在的前药相同的前药，
并且当R1和R2在相邻的碳上时，它们可以一起形成饱和或不饱和的烷基、芳族或杂芳族环
每个R3独立地为芳基、杂芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基或C2-10炔基，其中的每一个未被取代或独立地被一个或多个选自以下组的取代基取代：R4、OH、OR4、SR4、S(O)R4、SO2R4、C(O)R4、C(O)OR4、OC(O)R4、OC(O)OR4、NH2、NHR4、NHC(O)R4、NR4C(O)R4、NHS(O)2R4、NR4S(O)2R4、NHC(O)OR4、NR4C(O)OR4、NHC(O)NH2、NHC(O)NHR4、NHC(O)N(R4)2、NR4C(O)N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2、C(O)NHOH、C(O)NHOR4、C(O)NHSO2R4、C(O)NR4SO2R4、SO2NH2、SO2NHR4、SO2N(R4)2、COOH、C(O)H、C(N)NH2、C(N)NHR4、C(N)N(R4)2、C(N)OH、C(N)OCH4、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)、环Sal单磷酸酯前药、CH2P(O)(OH)2、CH2P(O)(OR4)2、CH2P(O)(OR4)(NR4)、CH2P(O)(NR4)2、CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)和CH2-环Sal单磷酸酯前药，
每个R4独立地选自芳基、杂芳基、芳基烷基、烷基芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基或C2-10炔基，其中每一个是未取代的或独立地被一个或多个选自以下组的取代基取代：R5、OH、OR5、SR5、S(O)R5、SO2R5、C(O)R5、C(O)OR5、OC(O)R5、OC(O)OR5、NH2、NHR5、NHC(O)R5、NR5C(O)R5、NHS(O)2R5、NR5S(O)2R5、NHC(O)OR5、NR5C(O)OR5、NHC(O)NH2、NHC(O)NHR5、NHC(O)N(R5)2、NR5C(O)N(R5)2、C(O)NH2、C(O)NHR5、C(O)N(R5)2、C(O)NHOH、C(O)NHOR5、C(O)NHSO2R5、C(O)NR5SO2R5、SO2NH2、SO2NHR5、SO2N(R5)2、COOH、C(O)H、C(N)NH2、C(N)NHR5、C(N)N(R5)2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)和环Sal单磷酸酯前药，
每个R5独立地为芳基、杂芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基或C2-10炔基，其中的每一个是未取代的或独立地被一个或多个选自以下组的取代基取代：R6、OH、OR6、SR6、S(O)R6、SO2R6、C(O)R6、C(O)OR6、OC(O)R6、OC(O)OR6、NH2、NHR6、NHC(O)R6、NR6C(O)R6、NHS(O)2R6、NR6S(O)2R6、NHC(O)OR6、NR6C(O)OR6、NHC(O)NH2、NHC(O)NHR6、NHC(O)N(R6)2、NR6C(O)N(R6)2、C(O)NH2、C(O)NHR6、C(O)N(R6)2、C(O)NHOH、C(O)NHOR6、C(O)NHSO2R6、C(O)NR6SO2R6、SO2NH2、SO2NHR6、SO2N(R6)2、COOH、C(O)H、C(N)NH2、C(N)NHR6、C(N)N(R6)2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br、I、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)和环Sal单磷酸酯前药，
每个R6独立地为芳基、杂芳基、C3-10环烷基、C3-10环烯基、杂环烷基、杂环烯基、C1-10烷基、C2-10烯基或C2-10炔基，其中的每一个是未取代的或独立地被一个或多个选自以下组的取代基取代：C1-10烷基、C2-10烯基、C2-10炔基、OH、NH2、C(O)NH2、C(O)NHOH、SO2NH2、COOH、C(O)H、C(N)NH2、C(N)OH、C(N)OCH3、CN、N3、NO2、CF3、CF2CF3、OCF3、OCF2CF3、卤素(F、Cl、Br或I)、P(O)(OH)2、P(O)(OR4)2、P(O)(OR4)(NR4)、P(O)(NR4)2、P(O)(OH)(OC1-10烷基-O-C1-20烷基)和环Sal单磷酸酯前药，
或其药学上可接受的盐或前药。
2.根据权利要求1所述的化合物，其中X和Z之一为-C(O)-、-SO2-或-NC(O)-，并且另一个为-NH-、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-或-O-。
3.根据权利要求1所述的化合物，其中X和Z之一为-C(O)-、-SO2-或-N(C(O)-，并且另一个为-CH2-、-CH(C1-6烷基)-、C(烷基)2-、-CH(C3-8环烷基)-、-CH(C2-6烯基、-CH(C2-6炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O烷基)-、-CH(NH2)-、-CH(NH烷基)-或-CH(C(O)NH2)-。
4.根据权利要求1所述的化合物，其中X和Z之一为-NH-、-N(NH2)-、-NH(OH)-、-N(烷基)-或-O-，并且另一个为-CH2-、-CH(C1-6烷基)-、C(烷基)2-、-CH(C3-8环烷基)-、-CH(C2-6烯基、-CH(C2-6炔基)-、-CH(芳基)-、-CH(杂芳基)-、-CF2-、-CCl2-、-CH(CF3)-、-CH(OH)-、-CH(O烷基)-、-CH(NH2)-、-CH(NH烷基)-或-CH(C(O)NH2)-。
5.根据权利要求1所述的化合物，其中X和Z之一为-NH-、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-，并且另一个为-C(O)-或-SO2-。
6.根据权利要求1所述的化合物，其中Y为-NH、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-或-O-。
7.根据权利要求6所述的化合物，其中Y为-NH、-N(NH2)-、-NH(OH)-、-N(C1-10烷基)-、-N(C3-10环烷基)-、-N(C2-10烯基)-、-N(C2-10炔基)-、-N(芳基)-或-N(杂芳基)-。
8.根据权利要求1所述的化合物，其中R1和R2之一是H、-CH2-膦酸酯、-CH2O-磷酸酯，其中术语磷酸酯包括单磷酸酯、二磷酸酯、三磷酸酯和稳定化的磷酸酯前药，术语膦酸酯包括与磷酸酯前药中存在的前药相同的前药。
9.根据权利要求1所述的化合物，其中R1和R2之一为H、-CH2P(O)(OH)2、-CH2P(O)(OH)(OR6)、-CH2P(O)(OR6)2、-CH2P(O)(OR6)(NR6)、-CH2P(O)(NR6)2、-CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)或-CH2-环Sal单磷酸酯前药。
10.根据权利要求9所述的化合物，其中R1和R2之一是膦酸酯、氨基磷酸酯、环Sal单磷酸酯前药，或具有式-CH2P(O)(OH)(OC1-10烷基-O-C1-20烷基)。
11.根据权利要求1所述的化合物，其中R1和R2之一为C(O)NHR4、C(O)(NR4)2、
其中R4为C1-10烷基、C3-10环烷基、C2-10烯基、C2-10炔基、C1-10卤代烷基、C1-10烷基-芳基或C1-10卤代烷基-芳基，并且m为0、1或2。
12.根据权利要求1所述的化合物，其中R1和R2之一为-C(O)-C1-10烷基、-C(O)-烷基芳基、-C(O)-杂环基-烷基芳基、-C(O)-杂环基-CH2-芳基、-C(O)-杂环基-CF2-芳基、-C(O)-环烷基-烷基芳基、-C(O)NHC1-10烷基、-C(O)NH-烷基芳基、-C(O)NH-杂环基-烷基芳基、-C(O)NH-杂环基-CF2-芳基、-C(O)NH-环烷基-烷基芳基、-SO2-C1-10烷基、-SO2-烷基芳基、-SO2-杂环基-烷基芳基、-SO2-杂环基-CF2-芳基或-SO2-环烷基-烷基芳基。
13.权利要求1所述的化合物，具有下式：
或其药学上可接受的盐或前药。
14.权利要求1所述的化合物，具有下式：
或其药学上可接受的盐或前药。
15.一种药物组合物，其包含根据权利要求1-14中任一项所述的化合物和药学上可接受的载体或赋形剂。
16.根据权利要求15所述的药物组合物，其中所述组合物是透皮组合物或纳米颗粒组合物。
17.根据权利要求15所述的药物组合物，其进一步包含不同于式(A)的第二视黄酸受体样孤儿受体(ROR)调节剂。
18.根据权利要求15所述的药物组合物，其进一步包含一种或多种用于治疗与ROR相关的病症的另外的活性剂。
19.根据权利要求15所述的药物组合物，其进一步包含一种或多种活性剂，所述活性剂选自用于治疗代谢性疾病、肝脏疾病、免疫紊乱、CNS失调或疾病以及癌症的药剂。
20.根据权利要求19所述的药物组合物，其中所述活性剂是抗糖尿病或抗胰岛素抵抗药剂。
21.根据权利要求20所述的药物组合物，其中所述抗糖尿病药或抗胰岛素抵抗药剂选自格列酮、磺酰脲、二甲双胍、胰岛素、胰岛素模拟物、DPP4抑制剂、GLP1受体激动剂、胰高血糖素受体拮抗剂和抗肥胖药剂。
22.根据权利要求18所述的药物组合物，其中所述另外的活性剂是抗TNF剂或免疫抑制性糖皮质激素。
23.根据权利要求18所述的药物组合物，其中所述另外的活性剂是铂化合物、长春花生物碱或其类似物、紫杉烷或氮芥。
24.根据权利要求18所述的药物组合物，其中所述另外的活性剂选自胆固醇生物合成抑制剂(HMG CoA还原酶抑制剂，例如洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、西立伐他汀、尼伐他汀和利伐他汀)；角鲨烯环氧酶抑制剂(例如特比萘芬)；血浆HDL升高剂(例如CETP抑制剂，例如安塞曲匹，R1658)；人过氧化物酶体增殖物激活受体(PPAR)γ激动剂(例如噻唑烷二酮，例如罗格列酮、曲格列酮和吡格列酮)；PPARα激动剂(例如氯贝特、非诺贝特和吉非布罗尼)；PPAR双α/γ激动剂(例如莫格他唑、阿格列扎、陪格列扎、elafibranor)；法呢类X受体(FXR)调节剂(例如奥贝胆酸、LMB763、LJN45等)；胆汁酸螯合剂(例如阴离子交换树脂或季胺(例如胆甾胺或考来替泊))；胆汁酸转运抑制剂(BATi)；烟酸、烟酰胺；胆固醇吸收抑制剂(例如伊泽替米)；酰基辅酶A：胆固醇O-酰基转移酶(ACAT)抑制剂(例如阿伐麦布)；选择性雌激素受体调节剂(例如雷洛昔芬或他莫昔芬)；LXRα或β激动剂、拮抗剂或部分激动剂(例如22(R)-羟基胆固醇、24(S)-羟基胆固醇、T0901317或GW3965)；微粒体甘油三酸酯转移蛋白(MTP)抑制剂、抗糖尿病药例如胰岛素和胰岛素类似物(例如LysPro胰岛素、包含胰岛素的吸入制剂；磺酰脲类和类似物(例如甲苯磺酰胺、氯丙酰胺、格列吡嗪、格列美脲、格列本脲、格列本、甲苯磺丁酰胺、对乙酰氨基甲酰胺、格列吡嗪)、双胍(例如二甲双胍或二甲双胍盐酸盐、苯乙双胍、丁二胍)α2拮抗剂和咪唑啉(例如咪达唑、伊格列醇、去甲利多尔、咪唑克生、依法洛宗、氟泊沙星)、噻唑烷二酮(例如吡格列酮盐酸盐、罗格列酮马来酸酯、西格列酮、曲格列酮或巴格列酮)、α-葡萄糖苷酶抑制剂(例如米格列醇、阿卡波糖、依帕司他或伏格列波糖)、美格替尼(例如瑞格列奈或那格列奈)、DPP-4抑制剂(例如磷酸西他列汀、沙格列汀、维格列汀、阿格列汀或登格列汀)、肠降血糖素(例如胰高血糖素样肽-1(GLP-1)受体激动剂(例如艾塞那肽(ByettaTM)、NN2211(利拉鲁肽)、GLP-1(7-36)酰胺及其类似物、GLP-1(7-37)及其类似物、AVE-0010(ZP-10)、R1583(塔斯波鲁肽)、GSK-716155(阿比鲁肽、GSK/人类基因组科学)、BRX-0585(辉瑞/Biorexis)和CJC-1134-PC(Exendin-4：PC-DACTM和葡萄糖依赖性促胰岛素肽(GIP))；淀粉纤维素激动剂(例如普兰林肽、AC-137)；胰岛素促泌剂(例如利诺格列、那格列奈、瑞格列奈、米格列奈钙水合钙或米格列奈钙)；SGLT-2抑制剂(例如达格列净(BMS)、索格列净(Kissei)、AVE 2268(Sanofi-Aventis)；葡糖激酶激活剂，例如WO 00/58293 A1中公开的化合物；抗肥胖药例如神经生长因子激动剂(例如，阿索开)、生长激素激动剂(例如AOD-9604)、肾上腺素摄取抑制剂(例如GW-320659)、5-HT(5-羟色胺)再摄取/转运抑制剂(例如百忧解)、5-HT/NA(5-羟色胺/去甲肾上腺素)再摄取抑制剂(例如西布曲明)、DA(多巴胺)再摄取抑制剂(例如巴泼鲁泼林)、5-HT、NA和DA再摄取阻滞剂、甾体植物提取物(例如P57)、NPY1或5(神经肽Y Y1或Y5)拮抗剂、NPY2(神经肽)Y Y2)激动剂、MC4(黑皮质素4)激动剂、CCK-A(胆囊收缩素A)激动剂、GHSR1a(生长激素促分泌素受体)拮抗剂/反向激动剂、生长素释放肽抗体、MCH1R(黑色素浓缩激素1R)拮抗剂(例如SNAP 7941)、MCH2R(黑色素浓缩激素2R)激动剂/拮抗剂、H3(组胺受体3)反向激动剂或拮抗剂、H1(组胺1受体)激动剂、FAS(脂肪酸合酶)抑制剂、ACC-1(乙酰辅酶A羧化酶-1)抑制剂、β3(β肾上腺素能受体3)激动剂、DGAT-2(二酰甘油酰基转移酶2)抑制剂、DGAT-1(二酰甘油酰基转移酶1)抑制剂、CRF(促肾上腺皮质激素释放因子)激动剂、甘丙肽拮抗剂、UCP-1(解偶联蛋白-1)、2或3种激活剂、瘦蛋白或瘦蛋白衍生物、鸦片样物质拮抗剂、食欲素拮抗剂、BRS3激动剂、GLP-1(胰高血糖素样肽1)激动剂、IL-6激动剂、α-MSH激动剂、AgRP拮抗剂、BRS3(蛙皮素受体亚型3)激动剂、5-HT1B激动剂，POMC拮抗剂、CNTF(纤毛神经营养因子或CNTF衍生物)、NN2211、托吡酯、糖皮质激素拮抗剂、Exendin-4激动剂、5-HT2C(5-羟色胺受体2C)激动剂(例如洛卡西林)、PDE(磷酸二酯酶)抑制剂、脂肪酸转运蛋白抑制剂、二羧酸盐转运蛋白抑制剂、葡萄糖转运蛋白抑制剂、CB-1(大麻素1受体)反向激动剂或拮抗剂(例如SR141716)、脂肪酶抑制剂(例如奥利司他)；环氧合酶2(COX-2)抑制剂(例如罗非考昔和塞来昔布)；凝血酶抑制剂(例如肝素、阿加曲班、美加仑、达比加群)；血小板聚集抑制剂(例如糖蛋白IIb/IIIa纤维蛋白原受体拮抗剂或阿司匹林)；维生素B6及其药学上可接受的盐；维生素B12；维生素E；叶酸或其药学上可接受的盐或酯；抗氧化剂维生素例如C、E和β-胡萝卜素；β受体阻滞剂(例如血管紧张素II受体拮抗剂如氯沙坦、厄贝沙坦或缬沙坦；抗降压素转化酶抑制剂例如依那普利和卡托普利；钙通道阻滞剂例如硝苯地平和地尔硫卓；内皮拮抗剂；阿司匹林；脂肪酸/胆汁酸结合物；半胱天冬酶抑制剂；免疫调节剂(Cenicriviroc等)；甲状腺激素受体调节剂(MB07811、MGL-3196等)；除LXR配体以外的可增强ATP结合盒式转运蛋白Al基因表达的试剂；以及双膦酸盐化合物(例如阿仑膦酸钠)。
25.根据权利要求18所述的药物组合物，其中所述另外的活性剂是改变宿主新陈代谢的药剂。
26.根据权利要求25所述的药物组合物，其中所述修饰宿主代谢的药剂选自克拉霉素、考比司他、茚地那韦、伊曲康唑、酮康唑、奈法唑酮、利托那韦、沙奎那韦、亚砜酮、替利霉素、阿吡匹坦、红霉素、氟康唑、维拉帕米、地尔硫卓、西咪替丁、胺碘酮、波普瑞韦、氯霉素、环丙沙星、地拉韦啶、二乙基二硫代氨基甲酸酯、氟伏沙明、孕二烯酮、伊马替尼、米贝拉地尔、米非司酮、诺氟沙星、诺氟西汀、特拉普拉韦和伏立康唑。
27.一种用于治疗或预防受视黄酸受体样孤儿受体(ROR)调节剂影响的疾病的方法，所述方法包括向需要治疗的患者施用有效治疗量的根据权利要求1-14中任一项所述的化合物。
28.根据权利要求27所述的方法，其中所述疾病是肝病或代谢性疾病。
29.根据权利要求28所述的方法，其中所述疾病选自脂质和胆固醇水平升高，特别是高LDL-胆固醇、高甘油三酸酯、低HDL-胆固醇、血脂异常、胆固醇吸收疾病、动脉粥样硬化疾病、冠状动脉疾病、脑血管动脉疾病、外周血管疾病、主动脉瘤、颈动脉粥样硬化病症、胆汁淤积性疾病、外周闭塞性疾病、缺血性中风、糖尿病，尤其是非胰岛素依赖型糖尿病、代谢综合征、糖尿病肾病、肥胖症、胆固醇胆结石病、胆汁淤积/纤维化肝脏、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、肝缺血再灌注损伤或非酒精性脂肪肝疾病(NAFLD)；自身免疫性疾病，例如但不限于类风湿性关节炎、强直性脊柱炎、红斑狼疮、牛皮癣、银屑病关节炎、特应性湿疹、炎症性肠病，例如克罗恩病、哮喘、粘膜利什曼病、多发性硬化症、系统性硬化、1型糖尿病、川崎病、桥本氏甲状腺炎、恶性贫血、慢性移植物抗宿主病、急性移植物抗宿主病、乳糜泻、特发性血小板减少性血栓性紫癜、重症肌无力、干燥综合征、硬皮病、溃疡性结肠炎、表皮增生、肾小球肾炎、慢阻塞性肺疾病(COPD)和肌萎缩性侧索硬化症。
30.根据权利要求27所述的方法，其中所述疾病是与ROR相关的中枢神经系统疾病(CNS)。
31.如权利要求30所述的方法，其中所述疾病是睡眠障碍、焦虑症或神经退行性疾病，例如帕金森氏症或阿尔茨海默氏病。
32.根据权利要求27所述的方法，其中所述疾病是癌症。
33.根据权利要求32所述的方法，其中所述癌症选自肝癌、结肠癌、前列腺癌、乳腺癌、淋巴癌、脑癌和髓样癌。
34.根据权利要求27所述的方法，其中所述疾病是非酒精性脂肪性肝炎或肝硬化。
35.根据权利要求27所述的方法，其中所述疾病是肥胖症。
36.根据权利要求27所述的方法，其中所述化合物是视黄酸受体样孤儿受体(ROR)α激动剂。
37.根据权利要求27所述的方法，其中所述化合物与第二种治疗剂组合或交替施用。
38.根据权利要求37所述的方法，其中所述第二治疗剂选自用于治疗代谢性疾病、肝脏疾病、免疫紊乱、CNS失调或疾病以及癌症的药剂。
39.根据权利要求38所述的方法，其中所述活性剂是抗糖尿病或抗胰岛素抵抗药剂。
40.根据权利要求39所述的方法，其中所述抗糖尿病药或抗胰岛素抵抗药剂选自格列酮、磺酰脲、二甲双胍、胰岛素、胰岛素模拟物、DPP4抑制剂、GLP1受体激动剂、胰高血糖素受体拮抗剂和抗肥胖药剂。
41.根据权利要求38所述的方法，其中所述另外的活性剂是抗TNF剂或免疫抑制性糖皮质激素。
42.根据权利要求38所述的方法，其中所述另外的活性剂是铂化合物、长春花生物碱或其类似物、紫杉烷或氮芥。
43.根据权利要求38所述的方法，其中所述另外的活性剂选自胆固醇生物合成抑制剂；角鲨烯环氧酶抑制剂；血浆HDL升高剂；人过氧化物酶体增殖物激活受体(PPAR)γ激动剂；PPARα激动剂；PPAR双α/γ激动剂；法呢类X受体(FXR)调节剂；胆汁酸螯合剂；胆汁酸转运抑制剂；烟酸、烟酰胺；胆固醇吸收抑制剂；酰基辅酶A：胆固醇O-酰基转移酶(ACAT)抑制剂；选择性雌激素受体调节剂；LXRα或β激动剂、拮抗剂或部分激动剂；微粒体甘油三酸酯转移蛋白(MTP)抑制剂、抗糖尿病药；SGLT-2抑制剂、索格列净、AVE 2268；葡糖激酶激活剂；抗肥胖药、生长激素激动剂、肾上腺素摄取抑制剂，5-羟色胺再摄取/转运抑制剂、5-HT/NA(5-羟色胺/去甲肾上腺素)再摄取抑制剂、多巴胺再摄取抑制剂、5-HT、NA和DA再摄取阻滞剂、甾体植物提取物、NPY1或5(神经肽Y1或Y5)拮抗剂、NPY2(神经肽Y2)激动剂、MC4(黑皮质素4)激动剂、CCK-A(胆囊收缩素A)激动剂、GHSR1a(生长激素促分泌素受体)拮抗剂/反向激动剂、生长素释放肽抗体、MCH1R(黑色素浓缩激素1R)拮抗剂、MCH2R(黑色素浓缩激素2R)激动剂/拮抗剂、H3(组胺受体3)反向激动剂或拮抗剂、H1(组胺1受体)激动剂、FAS(脂肪酸合酶)抑制剂、ACC-1(乙酰辅酶A羧化酶-1)抑制剂、β3(β肾上腺素能受体3)激动剂、DGAT-2(二酰甘油酰基转移酶2)抑制剂、DGAT-1(二酰甘油酰基转移酶1)抑制剂、CRF(促肾上腺皮质激素释放因子)激动剂、甘丙肽拮抗剂、UCP-1、2或3(解偶联蛋白-1、2或3)激活剂、瘦蛋白、瘦蛋白衍生物、鸦片样物质拮抗剂、食欲素拮抗剂、BRS3激动剂、GLP-1(胰高血糖素样肽1)激动剂、IL-6激动剂、α-MSH激动剂、AgRP拮抗剂、BRS3(蛙皮素受体亚型3)激动剂、5-HT1B激动剂，POMC拮抗剂、纤毛神经营养因子、NN2211、托吡酯、糖皮质激素拮抗剂、Exendin-4激动剂、5-羟色胺受体2C激动剂、磷酸二酯酶抑制剂、脂肪酸转运蛋白抑制剂、二羧酸盐转运蛋白抑制剂、葡萄糖转运蛋白抑制剂、大麻素1受体反向激动剂或拮抗剂、脂肪酶抑制剂；环氧合酶2抑制剂；凝血酶抑制剂；血小板聚集抑制剂；维生素B6及其药学上可接受的盐；维生素B12；叶酸或其药学上可接受的盐或酯；抗氧化剂维生素；β受体阻滞剂；抗降压素转化酶抑制剂；钙通道阻滞剂；内皮拮抗剂；阿司匹林；脂肪酸/胆汁酸结合物；半胱天冬酶抑制剂；甲状腺激素受体调节剂；除LXR配体以外的可增强ATP结合盒式转运蛋白Al基因表达的试剂；以及双膦酸盐化合物。
44.根据权利要求38所述的方法，其中所述另外的活性剂是改变宿主新陈代谢的药剂。
45.根据权利要求44所述的方法，其中所述修饰宿主代谢的药剂选自克拉霉素、考比司他、茚地那韦、伊曲康唑、酮康唑、奈法唑酮、利托那韦、沙奎那韦、亚砜酮、替利霉素、阿吡匹坦、红霉素、氟康唑、维拉帕米、地尔硫卓、西咪替丁、胺碘酮、波普瑞韦、氯霉素、环丙沙星、地拉韦啶、二乙基二硫代氨基甲酸酯、氟伏沙明、孕二烯酮、伊马替尼、米贝拉地尔、米非司酮、诺氟沙星、诺氟西汀、特拉普拉韦和伏立康唑。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201862666288P | 2018-05-03 | 2018-05-03 | |
| US62/666,288 | 2018-05-03 | ||
| PCT/US2019/030680 WO2019213584A1 (en) | 2018-05-03 | 2019-05-03 | Modulators of orphan nuclear receptors for nash and other metabolic disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112334137A true CN112334137A (zh) | 2021-02-05 |
Family
ID=68386695
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980044009.3A Pending CN112334137A (zh) | 2018-05-03 | 2019-05-03 | 用于nash和其他代谢紊乱的孤儿核受体调节剂 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20210052603A1 (zh) |
| EP (1) | EP3787631A4 (zh) |
| CN (1) | CN112334137A (zh) |
| CA (1) | CA3099138A1 (zh) |
| WO (1) | WO2019213584A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3098177A1 (en) * | 2020-10-30 | 2022-04-30 | Emory University | ORPHAN NUCLEAR RECEPTOR MODULATORS FOR USE IN THE TREATMENT OF PANCREATITIS, GLIOBLASTOMA, SARCOPENIA, STROKE AND BRAIN INJURIES |
| WO2022187349A1 (en) * | 2021-03-02 | 2022-09-09 | The Regents Of The University Of California | Combinatory therapy for preventing, inhibiting, treating, or reducing aneurysms |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017048954A1 (en) * | 2015-09-15 | 2017-03-23 | Assembly Biosciences, Inc. | Hepatitis b core protein modulators |
| CN109071544A (zh) * | 2017-02-23 | 2018-12-21 | 福建广生堂药业股份有限公司 | 三并环类化合物及其应用 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004076424A1 (en) * | 2003-02-27 | 2004-09-10 | Abbott Laboratories | Heterocyclic kinase inhibitors |
| US20040254159A1 (en) * | 2003-02-27 | 2004-12-16 | Hasvold Lisa A. | Heterocyclic kinase inhibitors |
| US20070105835A1 (en) * | 2005-11-07 | 2007-05-10 | Kazantsev Aleksey G | Compositions and methods for modulating poly(ADP-ribose) polymerase activity |
| US8202989B2 (en) * | 2009-01-12 | 2012-06-19 | Council Of Scientific And Industrial Research | One step process for the preparation of substituted 5, 10-dihydrodibenzo [b,e][1, 4]diazepine-11-ones |
| WO2015138895A1 (en) * | 2014-03-13 | 2015-09-17 | Indiana University Research And Technology Corporation | Hepatitis b core protein allosteric modulators |
-
2019
- 2019-05-03 CA CA3099138A patent/CA3099138A1/en active Pending
- 2019-05-03 US US17/051,332 patent/US20210052603A1/en active Pending
- 2019-05-03 CN CN201980044009.3A patent/CN112334137A/zh active Pending
- 2019-05-03 EP EP19796416.6A patent/EP3787631A4/en active Pending
- 2019-05-03 WO PCT/US2019/030680 patent/WO2019213584A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017048954A1 (en) * | 2015-09-15 | 2017-03-23 | Assembly Biosciences, Inc. | Hepatitis b core protein modulators |
| CN109071544A (zh) * | 2017-02-23 | 2018-12-21 | 福建广生堂药业股份有限公司 | 三并环类化合物及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| YONG-HYUN HAN: "RORa Decreases Oxidative Stress Through the Induction of SOD2 and GPx1 Expression and Thereby Protects Against Nonalcoholic Steatohepatitis in Mice" * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2019213584A1 (en) | 2019-11-07 |
| CA3099138A1 (en) | 2019-11-07 |
| US20210052603A1 (en) | 2021-02-25 |
| EP3787631A4 (en) | 2022-01-19 |
| EP3787631A1 (en) | 2021-03-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11629125B2 (en) | Elimination of hepatitis b virus with antiviral agents | |
| AU2017202625B2 (en) | Targeted therapeutics | |
| CN114026067A (zh) | 用于治疗冠状病毒和小核糖核酸病毒感染的肽模拟物 | |
| US20230000893A1 (en) | Antiviral Agents and Nucleoside Analogs for Treatment of Zika Virus | |
| CN101006065B (zh) | 抑制bcl蛋白与结合伴侣的相互作用的化合物和方法 | |
| JP7098214B2 (ja) | 非アルコール性脂肪性肝炎（ＮＡＳＨ）の処置のためのｓＧＣ刺激物質の使用 | |
| JP6402393B2 (ja) | 抗悪性腫瘍剤組成物 | |
| EP3691620B1 (en) | P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd | |
| CA2941618A1 (en) | Targeted therapeutics | |
| TW201040181A (en) | Macrocyclic serine protease inhibitors | |
| US9464093B2 (en) | Substituted imidazo[4',5':4,5]cyclopenta[1,2-e]pyrrolo[1,2-a]pyrazines and oxazolo[4',5':4,5]cyclopenta[1,2-e]pyrrolo[1,2-a]pyrazines for treating brain cancer | |
| CN112334137A (zh) | 用于nash和其他代谢紊乱的孤儿核受体调节剂 | |
| EP3493848B1 (en) | Heterocyclic diamidines | |
| TW201609094A (zh) | 治療癌症之新穎方法 | |
| EP3009424B1 (en) | Bicyclic nitrogen-containing aromatic heterocyclic amide compound | |
| TWI335219B (en) | Virus therapeutic drug | |
| US20220331445A1 (en) | High density lipoprotein-like nanoparticles as inducers of ferroptosis in cancer | |
| WO2022094435A1 (en) | Modulators of orphan nuclear receptors for treating pancreatitis, glioblastoma, sarcopenia and stroke | |
| AU2007289232A1 (en) | Therapeutic methods using WRN binding molecules | |
| WO2017163243A1 (en) | Modulation of calcium channel splice variant in cancer therapy | |
| WO2023216871A1 (zh) | Egfr抑制剂及其用途 | |
| TW202408544A (zh) | 包含myc調節之組合療法 | |
| CN117618442A (zh) | Rho激酶抑制剂Fasudil在抑制幻觉作用中的新用途 | |
| KR20150036215A (ko) | 퀴논 화합물 및 암의 치료를 위한 그것의 용도 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |