EA015675B1 - Производные циклогексилпиразол-лактама в качестве ингибиторов 11-бета-гидроксистероиддегидрогеназы 1 - Google Patents

Info

Publication number

EA015675B1

EA015675B1 EA200870460A EA200870460A EA015675B1 EA 015675 B1 EA015675 B1 EA 015675B1 EA 200870460 A EA200870460 A EA 200870460A EA 200870460 A EA200870460 A EA 200870460A EA 015675 B1 EA015675 B1 EA 015675B1

Authority

EA

Eurasian Patent Office

Prior art keywords

mmol

dichloro

tetrahydro

pyrrolidin

indazol

Prior art date

2006-04-21

Links

• Espacenet
• Global Dossier
• Discuss

• 239000003112 inhibitor Substances 0.000 title description 12
• 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 title 1
• 101710186107 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 177
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
• -1 3,5-dichloro-4'-fluoro [1,1'-biphenyl] -4yl Chemical group 0.000 claims description 179
• 239000000460 chlorine Substances 0.000 claims description 61
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 60
• 150000003839 salts Chemical class 0.000 claims description 50
• 229910052757 nitrogen Inorganic materials 0.000 claims description 31
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 15
• 239000001257 hydrogen Substances 0.000 claims description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims description 14
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000005843 halogen group Chemical group 0.000 claims description 6
• 150000002431 hydrogen Chemical class 0.000 claims description 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 3
• 239000011737 fluorine Substances 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 238000002441 X-ray diffraction Methods 0.000 claims description 2
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
• 125000003545 alkoxy group Chemical group 0.000 claims 1
• 230000008520 organization Effects 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 179
• 238000000034 method Methods 0.000 abstract description 54
• 206010012601 diabetes mellitus Diseases 0.000 abstract description 26
• 230000000694 effects Effects 0.000 abstract description 23
• 208000001145 Metabolic Syndrome Diseases 0.000 abstract description 22
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 abstract description 22
• 208000008589 Obesity Diseases 0.000 abstract description 11
• 235000020824 obesity Nutrition 0.000 abstract description 11
• 201000001421 hyperglycemia Diseases 0.000 abstract description 8
• 206010020772 Hypertension Diseases 0.000 abstract description 7
• 229910052740 iodine Inorganic materials 0.000 abstract description 3
• 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 2
• 239000005557 antagonist Substances 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 295
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 294
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 134
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 122
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 112
• 239000000243 solution Substances 0.000 description 112
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 107
• 239000007787 solid Substances 0.000 description 106
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
• 239000011541 reaction mixture Substances 0.000 description 101
• 239000000047 product Substances 0.000 description 97
• 239000012074 organic phase Substances 0.000 description 83
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 78
• 239000002904 solvent Substances 0.000 description 73
• 238000006243 chemical reaction Methods 0.000 description 65
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
• 239000012267 brine Substances 0.000 description 47
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
• 229910052938 sodium sulfate Inorganic materials 0.000 description 38
• 235000011152 sodium sulphate Nutrition 0.000 description 38
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 36
• KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 32
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 238000011282 treatment Methods 0.000 description 30
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 29
• 238000004587 chromatography analysis Methods 0.000 description 29
• 239000003153 chemical reaction reagent Substances 0.000 description 28
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 28
• 239000000725 suspension Substances 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 150000001412 amines Chemical class 0.000 description 26
• 239000012043 crude product Substances 0.000 description 26
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
• 239000000377 silicon dioxide Substances 0.000 description 24
• 238000005481 NMR spectroscopy Methods 0.000 description 22
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 22
• 238000001914 filtration Methods 0.000 description 22
• JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 22
• 238000003756 stirring Methods 0.000 description 22
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 21
• 208000035475 disorder Diseases 0.000 description 20
• 239000012044 organic layer Substances 0.000 description 20
• 239000000741 silica gel Substances 0.000 description 20
• 229910002027 silica gel Inorganic materials 0.000 description 20
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
• 239000008346 aqueous phase Substances 0.000 description 19
• 230000002829 reductive effect Effects 0.000 description 19
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• 239000003921 oil Substances 0.000 description 18
• 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 17
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
• 238000010898 silica gel chromatography Methods 0.000 description 17
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
• 238000004458 analytical method Methods 0.000 description 16
• 201000010099 disease Diseases 0.000 description 16
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
• 241000124008 Mammalia Species 0.000 description 15
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 15
• VODXDMVTXFOYGV-UHFFFAOYSA-N 3-[(2,6-dichloro-4-methoxyphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound ClC1=CC(OC)=CC(Cl)=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 VODXDMVTXFOYGV-UHFFFAOYSA-N 0.000 description 14
• 229960000890 hydrocortisone Drugs 0.000 description 14
• 239000000543 intermediate Substances 0.000 description 14
• 229920006395 saturated elastomer Polymers 0.000 description 14
• 229910000029 sodium carbonate Inorganic materials 0.000 description 14
• 102000004877 Insulin Human genes 0.000 description 13
• 108090001061 Insulin Proteins 0.000 description 13
• 239000006260 foam Substances 0.000 description 13
• 229940125396 insulin Drugs 0.000 description 13
• 239000010410 layer Substances 0.000 description 13
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 13
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• 150000001299 aldehydes Chemical class 0.000 description 12
• 230000014759 maintenance of location Effects 0.000 description 12
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 12
• LQGZTMQWGJRWCD-UHFFFAOYSA-N phenoxybenzene trifluoromethanesulfonic acid Chemical compound FC(S(=O)(=O)O)(F)F.C1(=CC=CC=C1)OC1=CC=CC=C1 LQGZTMQWGJRWCD-UHFFFAOYSA-N 0.000 description 12
• 229910000027 potassium carbonate Inorganic materials 0.000 description 12
• 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 11
• 239000000706 filtrate Substances 0.000 description 11
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
• 239000007858 starting material Substances 0.000 description 11
• 239000000126 substance Substances 0.000 description 11
• 208000001072 type 2 diabetes mellitus Diseases 0.000 description 11
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
• 230000005764 inhibitory process Effects 0.000 description 10
• 239000012299 nitrogen atmosphere Substances 0.000 description 10
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 10
• FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 9
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
• MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 9
• MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
• 241000699670 Mus sp. Species 0.000 description 9
• UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 9
• 239000012298 atmosphere Substances 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 229960004544 cortisone Drugs 0.000 description 9
• 239000012972 dimethylethanolamine Substances 0.000 description 9
• 238000003821 enantio-separation Methods 0.000 description 9
• 238000005984 hydrogenation reaction Methods 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 8
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• 229910002091 carbon monoxide Inorganic materials 0.000 description 8
• 230000002401 inhibitory effect Effects 0.000 description 8
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
• 235000019341 magnesium sulphate Nutrition 0.000 description 8
• XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 8
• 229960003105 metformin Drugs 0.000 description 8
• 238000000746 purification Methods 0.000 description 8
• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 8
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 8
• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 8
• 201000001320 Atherosclerosis Diseases 0.000 description 7
• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 7
• 102000004190 Enzymes Human genes 0.000 description 7
• 108090000790 Enzymes Proteins 0.000 description 7
• 241000282412 Homo Species 0.000 description 7
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 7
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
• 229940100389 Sulfonylurea Drugs 0.000 description 7
• 238000006069 Suzuki reaction reaction Methods 0.000 description 7
• 108010004469 allophycocyanin Proteins 0.000 description 7
• 238000001816 cooling Methods 0.000 description 7
• 229940079593 drug Drugs 0.000 description 7
• 238000010992 reflux Methods 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• ZIOZRXDIMAJBRX-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dichloro-5-(4-fluorophenyl)benzene Chemical group C1=CC(F)=CC=C1C1=CC(Cl)=C(CBr)C(Cl)=C1 ZIOZRXDIMAJBRX-UHFFFAOYSA-N 0.000 description 6
• NTXARXYZKVJZBF-UHFFFAOYSA-N 3-[(2,6-dichloro-4-hydroxyphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound ClC1=CC(O)=CC(Cl)=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 NTXARXYZKVJZBF-UHFFFAOYSA-N 0.000 description 6
• XTWQGFNPJUNTFD-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indazol-5-amine Chemical compound C1C(N)CCC2=C1C=NN2 XTWQGFNPJUNTFD-UHFFFAOYSA-N 0.000 description 6
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• 208000006011 Stroke Diseases 0.000 description 6
• 229910021529 ammonia Inorganic materials 0.000 description 6
• 229910052786 argon Inorganic materials 0.000 description 6
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
• 235000011089 carbon dioxide Nutrition 0.000 description 6
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
• MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
• HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
• 239000012230 colorless oil Substances 0.000 description 6
• 208000029078 coronary artery disease Diseases 0.000 description 6
• AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 6
• 150000002148 esters Chemical class 0.000 description 6
• 239000012458 free base Substances 0.000 description 6
• 150000002576 ketones Chemical class 0.000 description 6
• 230000007823 neuropathy Effects 0.000 description 6
• 201000001119 neuropathy Diseases 0.000 description 6
• 208000033808 peripheral neuropathy Diseases 0.000 description 6
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
• 238000002360 preparation method Methods 0.000 description 6
• 238000010791 quenching Methods 0.000 description 6
• 239000000523 sample Substances 0.000 description 6
• 238000000926 separation method Methods 0.000 description 6
• 235000012239 silicon dioxide Nutrition 0.000 description 6
• 239000011734 sodium Substances 0.000 description 6
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 6
• 235000019345 sodium thiosulphate Nutrition 0.000 description 6
• YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 6
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
• 238000012360 testing method Methods 0.000 description 6
• 238000004809 thin layer chromatography Methods 0.000 description 6
• 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 6
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
• 239000004342 Benzoyl peroxide Substances 0.000 description 5
• OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 5
• 206010022489 Insulin Resistance Diseases 0.000 description 5
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
• 239000002253 acid Substances 0.000 description 5
• 239000012190 activator Substances 0.000 description 5
• 150000008064 anhydrides Chemical class 0.000 description 5
• 235000019400 benzoyl peroxide Nutrition 0.000 description 5
• 125000005620 boronic acid group Chemical class 0.000 description 5
• 210000004027 cell Anatomy 0.000 description 5
• 239000003795 chemical substances by application Substances 0.000 description 5
• 239000012141 concentrate Substances 0.000 description 5
• 239000013078 crystal Substances 0.000 description 5
• 238000011161 development Methods 0.000 description 5
• 230000018109 developmental process Effects 0.000 description 5
• 238000001704 evaporation Methods 0.000 description 5
• 230000008020 evaporation Effects 0.000 description 5
• 238000004949 mass spectrometry Methods 0.000 description 5
• 239000012071 phase Substances 0.000 description 5
• 239000002244 precipitate Substances 0.000 description 5
• 125000006239 protecting group Chemical group 0.000 description 5
• 210000002966 serum Anatomy 0.000 description 5
• 238000010561 standard procedure Methods 0.000 description 5
• 125000001424 substituent group Chemical group 0.000 description 5
• 238000001308 synthesis method Methods 0.000 description 5
• 230000029663 wound healing Effects 0.000 description 5
• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 4
• SBTZGBGHYGBMRX-UHFFFAOYSA-N 1,3-dichloro-5-(4-fluorophenyl)-2-methylbenzene Chemical group C1=C(Cl)C(C)=C(Cl)C=C1C1=CC=C(F)C=C1 SBTZGBGHYGBMRX-UHFFFAOYSA-N 0.000 description 4
• WSGURAYTCUVDQL-UHFFFAOYSA-N 5-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC=C2NN=CC2=C1 WSGURAYTCUVDQL-UHFFFAOYSA-N 0.000 description 4
• 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 4
• 101000976075 Homo sapiens Insulin Proteins 0.000 description 4
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
• CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
• 239000004743 Polypropylene Substances 0.000 description 4
• 235000019270 ammonium chloride Nutrition 0.000 description 4
• 239000003472 antidiabetic agent Substances 0.000 description 4
• 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
• 210000004369 blood Anatomy 0.000 description 4
• 239000008280 blood Substances 0.000 description 4
• 230000036755 cellular response Effects 0.000 description 4
• 230000003247 decreasing effect Effects 0.000 description 4
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
• 239000003085 diluting agent Substances 0.000 description 4
• 238000010828 elution Methods 0.000 description 4
• 239000000284 extract Substances 0.000 description 4
• 230000037406 food intake Effects 0.000 description 4
• 235000012631 food intake Nutrition 0.000 description 4
• 229960004580 glibenclamide Drugs 0.000 description 4
• 239000008103 glucose Substances 0.000 description 4
• 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 description 4
• 230000002641 glycemic effect Effects 0.000 description 4
• 238000004128 high performance liquid chromatography Methods 0.000 description 4
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
• PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 4
• 239000011777 magnesium Substances 0.000 description 4
• 208000030159 metabolic disease Diseases 0.000 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 description 4
• 229960000698 nateglinide Drugs 0.000 description 4
• 239000000546 pharmaceutical excipient Substances 0.000 description 4
• 229920001155 polypropylene Polymers 0.000 description 4
• 238000000634 powder X-ray diffraction Methods 0.000 description 4
• 239000011347 resin Substances 0.000 description 4
• 229920005989 resin Polymers 0.000 description 4
• 208000024891 symptom Diseases 0.000 description 4
• 208000011580 syndromic disease Diseases 0.000 description 4
• 238000003786 synthesis reaction Methods 0.000 description 4
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
• 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 description 3
• WWFRBIPLCLSKNH-UHFFFAOYSA-N 2,6-dichloro-4-hydroxybenzaldehyde Chemical compound OC1=CC(Cl)=C(C=O)C(Cl)=C1 WWFRBIPLCLSKNH-UHFFFAOYSA-N 0.000 description 3
• SZTBWTOKHBQRKC-UHFFFAOYSA-N 2-(3,5-dichloro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C1=C(Cl)C(C)=C(Cl)C=C1B1OC(C)(C)C(C)(C)O1 SZTBWTOKHBQRKC-UHFFFAOYSA-N 0.000 description 3
• KBAGYDQLZMGHMT-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dichloro-5-methoxybenzene Chemical compound COC1=CC(Cl)=C(CBr)C(Cl)=C1 KBAGYDQLZMGHMT-UHFFFAOYSA-N 0.000 description 3
• AWLPPBSWOMXWGA-UHFFFAOYSA-N 2-[1,2,2-tris(carboxymethylsulfanyl)ethylsulfanyl]acetic acid Chemical compound OC(=O)CSC(SCC(O)=O)C(SCC(O)=O)SCC(O)=O AWLPPBSWOMXWGA-UHFFFAOYSA-N 0.000 description 3
• RMKSYSZDGNFLNL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indazol-4-amine Chemical compound NC1CCCC2=C1C=NN2 RMKSYSZDGNFLNL-UHFFFAOYSA-N 0.000 description 3
• WOALOICTMCSWHN-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indazol-7-amine Chemical compound NC1CCCC2=C1NN=C2 WOALOICTMCSWHN-UHFFFAOYSA-N 0.000 description 3
• KMUKXPQVPQUCDB-UHFFFAOYSA-N 4-(trifluoromethyl)piperidine;hydrochloride Chemical compound Cl.FC(F)(F)C1CCNCC1 KMUKXPQVPQUCDB-UHFFFAOYSA-N 0.000 description 3
• 208000004611 Abdominal Obesity Diseases 0.000 description 3
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
• 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 3
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
• 229910052693 Europium Inorganic materials 0.000 description 3
• 102000051325 Glucagon Human genes 0.000 description 3
• 108060003199 Glucagon Proteins 0.000 description 3
• 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 description 3
• 229910004373 HOAc Inorganic materials 0.000 description 3
• XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
• 238000010521 absorption reaction Methods 0.000 description 3
• 229960002632 acarbose Drugs 0.000 description 3
• 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 description 3
• 239000003888 alpha glucosidase inhibitor Substances 0.000 description 3
• 239000000908 ammonium hydroxide Substances 0.000 description 3
• 229940125708 antidiabetic agent Drugs 0.000 description 3
• 239000003524 antilipemic agent Substances 0.000 description 3
• 239000007864 aqueous solution Substances 0.000 description 3
• OBZHEBDUNPOCJG-SZTGPWMUSA-N carbenoxolone Chemical compound C([C@H]1C2=CC(=O)[C@@H]34)[C@](C)(C(O)=O)CC[C@@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@H]1[C@@]3(C)CC[C@@H](OC(=O)CCC(O)=O)C1(C)C OBZHEBDUNPOCJG-SZTGPWMUSA-N 0.000 description 3
• 229960000530 carbenoxolone Drugs 0.000 description 3
• 125000004432 carbon atom Chemical group C* 0.000 description 3
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
• 238000007872 degassing Methods 0.000 description 3
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
• 238000001035 drying Methods 0.000 description 3
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
• OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 3
• 239000012467 final product Substances 0.000 description 3
• MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=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](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 3
• 229960004666 glucagon Drugs 0.000 description 3
• 239000003862 glucocorticoid Substances 0.000 description 3
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
• 125000004537 indazol-5-yl group Chemical group N1N=CC2=CC(=CC=C12)* 0.000 description 3
• 150000003951 lactams Chemical class 0.000 description 3
• 150000002596 lactones Chemical class 0.000 description 3
• 210000004185 liver Anatomy 0.000 description 3
• 244000144972 livestock Species 0.000 description 3
• 239000000463 material Substances 0.000 description 3
• 239000002609 medium Substances 0.000 description 3
• 230000001575 pathological effect Effects 0.000 description 3
• JDKQTIKEGOOXTJ-UHFFFAOYSA-N pent-4-enoyl chloride Chemical compound ClC(=O)CCC=C JDKQTIKEGOOXTJ-UHFFFAOYSA-N 0.000 description 3
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
• 235000011056 potassium acetate Nutrition 0.000 description 3
• 239000000843 powder Substances 0.000 description 3
• 230000002265 prevention Effects 0.000 description 3
• 108090000623 proteins and genes Proteins 0.000 description 3
• 238000001953 recrystallisation Methods 0.000 description 3
• 238000006268 reductive amination reaction Methods 0.000 description 3
• 229960002354 repaglinide Drugs 0.000 description 3
• 239000012279 sodium borohydride Substances 0.000 description 3
• 229910000033 sodium borohydride Inorganic materials 0.000 description 3
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
• 239000000758 substrate Substances 0.000 description 3
• 229940037128 systemic glucocorticoids Drugs 0.000 description 3
• 230000001225 therapeutic effect Effects 0.000 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 description 3
• 229960001641 troglitazone Drugs 0.000 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 description 3
• GZPKMEKJXBJIEZ-UHFFFAOYSA-N (2,6-dichloro-4-methoxyphenyl)methanol Chemical compound COC1=CC(Cl)=C(CO)C(Cl)=C1 GZPKMEKJXBJIEZ-UHFFFAOYSA-N 0.000 description 2
• WNRSJMUEQPXEDJ-UHFFFAOYSA-N (2,6-dimethyl-4-phenylmethoxyphenyl)methanol Chemical compound CC1=C(CO)C(C)=CC(OCC=2C=CC=CC=2)=C1 WNRSJMUEQPXEDJ-UHFFFAOYSA-N 0.000 description 2
• IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
• HQPKIDVCBSSUON-UHFFFAOYSA-N (4,4-difluoropiperidin-1-yl)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(C(=O)N2CCC(F)(F)CC2)C=C1 HQPKIDVCBSSUON-UHFFFAOYSA-N 0.000 description 2
• YCQQXJQRTUMDOM-UHFFFAOYSA-N (4-bromophenyl)-(4,4-difluoropiperidin-1-yl)methanone Chemical compound C1CC(F)(F)CCN1C(=O)C1=CC=C(Br)C=C1 YCQQXJQRTUMDOM-UHFFFAOYSA-N 0.000 description 2
• ZDCHPJBPSYAZEP-UHFFFAOYSA-N (4-bromophenyl)-[4-(trifluoromethyl)piperidin-1-yl]methanone Chemical compound C1CC(C(F)(F)F)CCN1C(=O)C1=CC=C(Br)C=C1 ZDCHPJBPSYAZEP-UHFFFAOYSA-N 0.000 description 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
• JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 2
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
• VKRKCBWIVLSRBJ-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decan-8-one Chemical compound C1CC(=O)CCC21OCCO2 VKRKCBWIVLSRBJ-UHFFFAOYSA-N 0.000 description 2
• FUVZDXDCPRQZSQ-UHFFFAOYSA-N 1,5,6,7-tetrahydroindazol-4-one Chemical compound O=C1CCCC2=C1C=NN2 FUVZDXDCPRQZSQ-UHFFFAOYSA-N 0.000 description 2
• 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
• YHGNNADYZQCMPZ-UHFFFAOYSA-N 1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one Chemical compound O=C1CCCN1C1CCC2(OCCO2)CC1 YHGNNADYZQCMPZ-UHFFFAOYSA-N 0.000 description 2
• JWCNYGFAYNMHPZ-UHFFFAOYSA-N 1-(5-nitroindazol-1-yl)ethanone Chemical compound [O-][N+](=O)C1=CC=C2N(C(=O)C)N=CC2=C1 JWCNYGFAYNMHPZ-UHFFFAOYSA-N 0.000 description 2
• ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
• DGAYFCFQKDUHQN-UHFFFAOYSA-N 1-bromo-2,4-dichloro-3-methylbenzene Chemical compound CC1=C(Cl)C=CC(Br)=C1Cl DGAYFCFQKDUHQN-UHFFFAOYSA-N 0.000 description 2
• TWXMGJINTMSISF-UHFFFAOYSA-N 1-chloro-3,4-difluoro-2-(iodomethyl)-5-(trifluoromethyl)benzene Chemical compound FC1=C(F)C(C(F)(F)F)=CC(Cl)=C1CI TWXMGJINTMSISF-UHFFFAOYSA-N 0.000 description 2
• UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 2
• KEJFADGISRFLFO-UHFFFAOYSA-N 1H-indazol-6-amine Chemical compound NC1=CC=C2C=NNC2=C1 KEJFADGISRFLFO-UHFFFAOYSA-N 0.000 description 2
• OTFFCAGPSWJBDK-UHFFFAOYSA-N 1h-indazol-7-amine Chemical compound NC1=CC=CC2=C1NN=C2 OTFFCAGPSWJBDK-UHFFFAOYSA-N 0.000 description 2
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
• FLHXTURECXRMQK-UHFFFAOYSA-N 2,6-dichloro-4-phenylmethoxybenzaldehyde Chemical compound ClC1=C(C=O)C(Cl)=CC(OCC=2C=CC=CC=2)=C1 FLHXTURECXRMQK-UHFFFAOYSA-N 0.000 description 2
• ZOSUBLBLLWVEBF-UHFFFAOYSA-N 2,6-dimethyl-4-phenylmethoxybenzaldehyde Chemical compound CC1=C(C=O)C(C)=CC(OCC=2C=CC=CC=2)=C1 ZOSUBLBLLWVEBF-UHFFFAOYSA-N 0.000 description 2
• GUXFHOKKFSZLTH-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dichloro-5-phenylmethoxybenzene Chemical compound ClC1=C(CBr)C(Cl)=CC(OCC=2C=CC=CC=2)=C1 GUXFHOKKFSZLTH-UHFFFAOYSA-N 0.000 description 2
• DZHIUWLZQNQNKD-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dimethyl-5-phenylmethoxybenzene Chemical compound CC1=C(CBr)C(C)=CC(OCC=2C=CC=CC=2)=C1 DZHIUWLZQNQNKD-UHFFFAOYSA-N 0.000 description 2
• ZMZVVVASCILFJL-UHFFFAOYSA-N 2-chloro-4-methoxy-1-methylbenzene Chemical compound COC1=CC=C(C)C(Cl)=C1 ZMZVVVASCILFJL-UHFFFAOYSA-N 0.000 description 2
• BNAZUYXBSXJPCE-UHFFFAOYSA-N 3-[(2,6-dichloro-4-methoxyphenyl)methyl]-1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one Chemical compound ClC1=CC(OC)=CC(Cl)=C1CC1C(=O)N(C2CCC3(CC2)OCCO3)CC1 BNAZUYXBSXJPCE-UHFFFAOYSA-N 0.000 description 2
• HFPDDWWTEMCKOM-UHFFFAOYSA-N 3-[(2,6-dichloro-4-methoxyphenyl)methyl]-1-(4-oxocyclohexyl)pyrrolidin-2-one Chemical compound ClC1=CC(OC)=CC(Cl)=C1CC1C(=O)N(C2CCC(=O)CC2)CC1 HFPDDWWTEMCKOM-UHFFFAOYSA-N 0.000 description 2
• ZOZRTWKUSOLRAA-UHFFFAOYSA-N 3-[(2,6-dichloro-4-methoxyphenyl)methyl]-1-[3-(dimethylaminomethylidene)-4-oxocyclohexyl]pyrrolidin-2-one Chemical compound ClC1=CC(OC)=CC(Cl)=C1CC1C(=O)N(C2CC(C(=O)CC2)=CN(C)C)CC1 ZOZRTWKUSOLRAA-UHFFFAOYSA-N 0.000 description 2
• GBZLDIDROONDRN-UHFFFAOYSA-N 3-[(2-chloro-4-hydroxyphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound ClC1=CC(O)=CC=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 GBZLDIDROONDRN-UHFFFAOYSA-N 0.000 description 2
• GXOCYUHGTZTTFQ-UHFFFAOYSA-N 3-[(4-bromo-2-chlorophenyl)methyl]-1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one Chemical compound ClC1=CC(Br)=CC=C1CC1C(=O)N(C2CCC3(CC2)OCCO3)CC1 GXOCYUHGTZTTFQ-UHFFFAOYSA-N 0.000 description 2
• VBPWHBGYHAWCSP-UHFFFAOYSA-N 3-[(4-bromo-2-chlorophenyl)methyl]-1-(4-oxocyclohexyl)pyrrolidin-2-one Chemical compound ClC1=CC(Br)=CC=C1CC1C(=O)N(C2CCC(=O)CC2)CC1 VBPWHBGYHAWCSP-UHFFFAOYSA-N 0.000 description 2
• AGOYTZLNJFTYKH-UHFFFAOYSA-N 3-[[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-1-(4-oxocyclohexyl)pyrrolidin-2-one Chemical compound C1=NN(C)C=C1C(C=C1Cl)=CC=C1CC1C(=O)N(C2CCC(=O)CC2)CC1 AGOYTZLNJFTYKH-UHFFFAOYSA-N 0.000 description 2
• NIQIPYGXPZUDDP-UHFFFAOYSA-N 3-aminocyclohexan-1-ol Chemical compound NC1CCCC(O)C1 NIQIPYGXPZUDDP-UHFFFAOYSA-N 0.000 description 2
• KMVPZFQPMBEGDF-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indazol-4-ol Chemical compound OC1CCCC2=NNC=C12 KMVPZFQPMBEGDF-UHFFFAOYSA-N 0.000 description 2
• LIDRLTJNPRPOFD-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-indazol-6-amine Chemical compound C1C(N)CCC2=C1NN=C2 LIDRLTJNPRPOFD-UHFFFAOYSA-N 0.000 description 2
• 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 description 2
• RAGVNCRGYFDBBA-UHFFFAOYSA-N 4-[3,5-dichloro-4-[[2-oxo-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-3-yl]methyl]phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(C=C1Cl)=CC(Cl)=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 RAGVNCRGYFDBBA-UHFFFAOYSA-N 0.000 description 2
• TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 2
• UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 2
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
• 208000011732 Abnormal glucose homeostasis Diseases 0.000 description 2
• 241000272517 Anseriformes Species 0.000 description 2
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
• ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
• 208000024172 Cardiovascular disease Diseases 0.000 description 2
• 206010065941 Central obesity Diseases 0.000 description 2
• 229910016523 CuKa Inorganic materials 0.000 description 2
• 208000032928 Dyslipidaemia Diseases 0.000 description 2
• 241000402754 Erythranthe moschata Species 0.000 description 2
• 206010019280 Heart failures Diseases 0.000 description 2
• 101000938676 Homo sapiens Liver carboxylesterase 1 Proteins 0.000 description 2
• 101000587820 Homo sapiens Selenide, water dikinase 1 Proteins 0.000 description 2
• 101000701815 Homo sapiens Spermidine synthase Proteins 0.000 description 2
• 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
• 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
• 206010060378 Hyperinsulinaemia Diseases 0.000 description 2
• 208000017170 Lipid metabolism disease Diseases 0.000 description 2
• 102000004895 Lipoproteins Human genes 0.000 description 2
• 108090001030 Lipoproteins Proteins 0.000 description 2
• 102100030817 Liver carboxylesterase 1 Human genes 0.000 description 2
• 241000948268 Meda Species 0.000 description 2
• 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 description 2
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
• ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 2
• MEWQTYBEZQAUHA-UHFFFAOYSA-N N=1N(C=C2CCCCC12)C(=O)O Chemical compound N=1N(C=C2CCCCC12)C(=O)O MEWQTYBEZQAUHA-UHFFFAOYSA-N 0.000 description 2
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
• 102000004257 Potassium Channel Human genes 0.000 description 2
• 208000017442 Retinal disease Diseases 0.000 description 2
• 206010038923 Retinopathy Diseases 0.000 description 2
• YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
• 241000282849 Ruminantia Species 0.000 description 2
• 102100037580 Sesquipedalian-1 Human genes 0.000 description 2
• 101710169844 Sesquipedalian-1 Proteins 0.000 description 2
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
• 102100030413 Spermidine synthase Human genes 0.000 description 2
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
• 229940123464 Thiazolidinedione Drugs 0.000 description 2
• JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 2
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
• FFWGDENAWCPASU-UHFFFAOYSA-N [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(C(=O)N2CCC(CC2)C(F)(F)F)C=C1 FFWGDENAWCPASU-UHFFFAOYSA-N 0.000 description 2
• BOGSOFADOWIECK-UHFFFAOYSA-N [N].C=1C=NNC=1 Chemical compound [N].C=1C=NNC=1 BOGSOFADOWIECK-UHFFFAOYSA-N 0.000 description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
• 230000002378 acidificating effect Effects 0.000 description 2
• 239000013543 active substance Substances 0.000 description 2
• 230000029936 alkylation Effects 0.000 description 2
• 238000005804 alkylation reaction Methods 0.000 description 2
• VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
• 210000000709 aorta Anatomy 0.000 description 2
• 239000012911 assay medium Substances 0.000 description 2
• IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
• 230000017531 blood circulation Effects 0.000 description 2
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
• 229910052794 bromium Inorganic materials 0.000 description 2
• 229910052799 carbon Inorganic materials 0.000 description 2
• 230000008859 change Effects 0.000 description 2
• 238000004296 chiral HPLC Methods 0.000 description 2
• 125000001309 chloro group Chemical group Cl* 0.000 description 2
• 238000004140 cleaning Methods 0.000 description 2
• 208000010877 cognitive disease Diseases 0.000 description 2
• 230000003920 cognitive function Effects 0.000 description 2
• 229940126142 compound 16 Drugs 0.000 description 2
• 125000004122 cyclic group Chemical group 0.000 description 2
• 230000001419 dependent effect Effects 0.000 description 2
• 238000010511 deprotection reaction Methods 0.000 description 2
• 238000002050 diffraction method Methods 0.000 description 2
• 238000010790 dilution Methods 0.000 description 2
• 239000012895 dilution Substances 0.000 description 2
• GZWVVCXUNQVSRI-UHFFFAOYSA-N ethyl 2-[(4-bromo-2-chlorophenyl)methyl]-4-oxobutanoate Chemical compound CCOC(=O)C(CC=O)CC1=CC=C(Br)C=C1Cl GZWVVCXUNQVSRI-UHFFFAOYSA-N 0.000 description 2
• DXFSEHTYQUXREM-UHFFFAOYSA-N ethyl 2-[(4-bromo-2-chlorophenyl)methyl]pent-4-enoate Chemical compound CCOC(=O)C(CC=C)CC1=CC=C(Br)C=C1Cl DXFSEHTYQUXREM-UHFFFAOYSA-N 0.000 description 2
• 230000005284 excitation Effects 0.000 description 2
• 239000012065 filter cake Substances 0.000 description 2
• 238000003818 flash chromatography Methods 0.000 description 2
• 125000001153 fluoro group Chemical group F* 0.000 description 2
• 239000012634 fragment Substances 0.000 description 2
• 239000011521 glass Substances 0.000 description 2
• 229960001381 glipizide Drugs 0.000 description 2
• 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 description 2
• 238000010438 heat treatment Methods 0.000 description 2
• 210000005119 human aortic smooth muscle cell Anatomy 0.000 description 2
• 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
• 230000003451 hyperinsulinaemic effect Effects 0.000 description 2
• 201000008980 hyperinsulinism Diseases 0.000 description 2
• 230000002779 inactivation Effects 0.000 description 2
• 239000004026 insulin derivative Substances 0.000 description 2
• 230000010354 integration Effects 0.000 description 2
• 239000011630 iodine Substances 0.000 description 2
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
• NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
• 238000002955 isolation Methods 0.000 description 2
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
• 208000017169 kidney disease Diseases 0.000 description 2
• 229910052745 lead Inorganic materials 0.000 description 2
• 230000037356 lipid metabolism Effects 0.000 description 2
• 150000002632 lipids Chemical class 0.000 description 2
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
• 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 description 2
• 229960004844 lovastatin Drugs 0.000 description 2
• 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 description 2
• 229950004994 meglitinide Drugs 0.000 description 2
• 230000004060 metabolic process Effects 0.000 description 2
• UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
• 229940098779 methanesulfonic acid Drugs 0.000 description 2
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
• 238000012544 monitoring process Methods 0.000 description 2
• 210000003205 muscle Anatomy 0.000 description 2
• HXRAMSFGUAOAJR-UHFFFAOYSA-N n,n,n',n'-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine Chemical compound CN(C)C(N(C)C)OC(C)(C)C HXRAMSFGUAOAJR-UHFFFAOYSA-N 0.000 description 2
• PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 description 2
• 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
• 238000002414 normal-phase solid-phase extraction Methods 0.000 description 2
• 230000003647 oxidation Effects 0.000 description 2
• 238000007254 oxidation reaction Methods 0.000 description 2
• 229910052763 palladium Inorganic materials 0.000 description 2
• 238000007911 parenteral administration Methods 0.000 description 2
• 239000008177 pharmaceutical agent Substances 0.000 description 2
• GRJHONXDTNBDTC-UHFFFAOYSA-N phenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CC=C1 GRJHONXDTNBDTC-UHFFFAOYSA-N 0.000 description 2
• IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 2
• HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
• 108020001213 potassium channel Proteins 0.000 description 2
• 230000003389 potentiating effect Effects 0.000 description 2
• 238000012545 processing Methods 0.000 description 2
• 102000004169 proteins and genes Human genes 0.000 description 2
• 239000010453 quartz Substances 0.000 description 2
• 230000004044 response Effects 0.000 description 2
• 239000012047 saturated solution Substances 0.000 description 2
• 230000028327 secretion Effects 0.000 description 2
• 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
• KGCLNLOAZIFEJL-UHFFFAOYSA-N tert-butyl 4-amino-4,5,6,7-tetrahydroindazole-2-carboxylate Chemical compound NC1CCCC2=NN(C(=O)OC(C)(C)C)C=C21 KGCLNLOAZIFEJL-UHFFFAOYSA-N 0.000 description 2
• HXIGRIBWAXSGHP-UHFFFAOYSA-N tert-butyl 4-azido-4,5,6,7-tetrahydroindazole-1-carboxylate Chemical compound [N-]=[N+]=NC1CCCC2=C1C=NN2C(=O)OC(C)(C)C HXIGRIBWAXSGHP-UHFFFAOYSA-N 0.000 description 2
• QJOSHZMHLKIDFL-UHFFFAOYSA-N tert-butyl 4-azido-4,5,6,7-tetrahydroindazole-2-carboxylate Chemical compound [N-]=[N+]=NC1CCCC2=NN(C(=O)OC(C)(C)C)C=C21 QJOSHZMHLKIDFL-UHFFFAOYSA-N 0.000 description 2
• AVXYUIOFKINYGL-UHFFFAOYSA-N tert-butyl 4-hydroxy-4,5,6,7-tetrahydroindazole-1-carboxylate Chemical compound OC1CCCC2=C1C=NN2C(=O)OC(C)(C)C AVXYUIOFKINYGL-UHFFFAOYSA-N 0.000 description 2
• OGAHMQMORUGKET-UHFFFAOYSA-N tert-butyl 4-hydroxy-4,5,6,7-tetrahydroindazole-2-carboxylate Chemical compound OC1CCCC2=NN(C(=O)OC(C)(C)C)C=C21 OGAHMQMORUGKET-UHFFFAOYSA-N 0.000 description 2
• GGZGEHFMODUSAW-UHFFFAOYSA-N tert-butyl 4-oxo-6,7-dihydro-5h-indazole-1-carboxylate Chemical compound C1CCC(=O)C2=C1N(C(=O)OC(C)(C)C)N=C2 GGZGEHFMODUSAW-UHFFFAOYSA-N 0.000 description 2
• MSCZNSXKVPJNCP-UHFFFAOYSA-N tert-butyl 4-oxo-6,7-dihydro-5h-indazole-2-carboxylate Chemical compound C1CCC(=O)C=2C1=NN(C(=O)OC(C)(C)C)C=2 MSCZNSXKVPJNCP-UHFFFAOYSA-N 0.000 description 2
• ZVYAFVOHYMRKHP-UHFFFAOYSA-N tert-butyl-(3,5-dichlorophenoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC(Cl)=CC(Cl)=C1 ZVYAFVOHYMRKHP-UHFFFAOYSA-N 0.000 description 2
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
• 229960005371 tolbutamide Drugs 0.000 description 2
• 238000012546 transfer Methods 0.000 description 2
• 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 2
• 238000005406 washing Methods 0.000 description 2
• OVPWEQROJNJHAG-UHFFFAOYSA-N (1-naphthalen-1-ylnaphthalen-2-yl)-diphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1)C1=CC=CC=C1 OVPWEQROJNJHAG-UHFFFAOYSA-N 0.000 description 1
• AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
• SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
• WTHWVGFNEDOQGB-UHFFFAOYSA-N (2,6-dichloro-4-phenylmethoxyphenyl)methanol Chemical compound C1=C(Cl)C(CO)=C(Cl)C=C1OCC1=CC=CC=C1 WTHWVGFNEDOQGB-UHFFFAOYSA-N 0.000 description 1
• 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 1
• WMUIIGVAWPWQAW-DEOSSOPVSA-N (2s)-2-ethoxy-3-{4-[2-(10h-phenoxazin-10-yl)ethoxy]phenyl}propanoic acid Chemical compound C1=CC(C[C@H](OCC)C(O)=O)=CC=C1OCCN1C2=CC=CC=C2OC2=CC=CC=C21 WMUIIGVAWPWQAW-DEOSSOPVSA-N 0.000 description 1
• QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
• WPGPRLVPWACBHW-UHFFFAOYSA-N (4-methoxy-4-oxobutyl)azanium;chloride Chemical compound Cl.COC(=O)CCCN WPGPRLVPWACBHW-UHFFFAOYSA-N 0.000 description 1
• KGFACZAHAULJPC-UHFFFAOYSA-N (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone;hydrochloride Chemical compound Cl.C1CN(C)CCN1C(=O)C1=CC=C(B2OC(C)(C)C(C)(C)O2)C=C1 KGFACZAHAULJPC-UHFFFAOYSA-N 0.000 description 1
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
• NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
• DMEDNTFWIHCBRK-UHFFFAOYSA-N 1,3-dichloro-2-methylbenzene Chemical compound CC1=C(Cl)C=CC=C1Cl DMEDNTFWIHCBRK-UHFFFAOYSA-N 0.000 description 1
• RYMMNSVHOKXTNN-UHFFFAOYSA-N 1,3-dichloro-5-methyl-benzene Natural products CC1=CC(Cl)=CC(Cl)=C1 RYMMNSVHOKXTNN-UHFFFAOYSA-N 0.000 description 1
• ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
• NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 description 1
• CXKUBSWJMNSYFO-UHFFFAOYSA-N 1,5-dichloro-5-methylcyclohexa-1,3-diene Chemical compound CC1(Cl)CC(Cl)=CC=C1 CXKUBSWJMNSYFO-UHFFFAOYSA-N 0.000 description 1
• CVVDRCJEVAKEJC-UHFFFAOYSA-N 1-(1,4-dioxaspiro[4.5]decan-8-yl)-3-[(2,4,6-trifluorophenyl)methyl]pyrrolidin-2-one Chemical compound FC1=CC(F)=CC(F)=C1CC1C(=O)N(C2CCC3(CC2)OCCO3)CC1 CVVDRCJEVAKEJC-UHFFFAOYSA-N 0.000 description 1
• UCNKMJWLJXQYMZ-UHFFFAOYSA-N 1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound O=C1CCCN1C1CC(C=NN2)=C2CC1 UCNKMJWLJXQYMZ-UHFFFAOYSA-N 0.000 description 1
• UIOYCWAQKOLSMA-UHFFFAOYSA-N 1-(bromomethyl)-2-chloro-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C(Cl)=C1 UIOYCWAQKOLSMA-UHFFFAOYSA-N 0.000 description 1
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
• JFTDNAXWZYOWHC-UHFFFAOYSA-N 1-bromo-3-(bromomethyl)-2,4-dichlorobenzene Chemical compound ClC1=CC=C(Br)C(Cl)=C1CBr JFTDNAXWZYOWHC-UHFFFAOYSA-N 0.000 description 1
• DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
• ZTNUECWBCHSTHA-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)-3,4-difluoro-5-(trifluoromethyl)benzene Chemical compound FC1=C(F)C(C(F)(F)F)=CC(Cl)=C1CCl ZTNUECWBCHSTHA-UHFFFAOYSA-N 0.000 description 1
• QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 1
• 238000005160 1H NMR spectroscopy Methods 0.000 description 1
• YDTDKKULPWTHRV-UHFFFAOYSA-N 1H-indazol-3-amine Chemical compound C1=CC=C2C(N)=NNC2=C1 YDTDKKULPWTHRV-UHFFFAOYSA-N 0.000 description 1
• NYOWYNSNCXRVNQ-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-indazole Chemical group C1=CCC2CNNC2=C1 NYOWYNSNCXRVNQ-UHFFFAOYSA-N 0.000 description 1
• CSDFHCDNAZPVKH-UHFFFAOYSA-N 2,3,3a,7a-tetrahydro-1h-indazole Chemical compound C1=CC=CC2CNNC21 CSDFHCDNAZPVKH-UHFFFAOYSA-N 0.000 description 1
• NTOIKDYVJIWVSU-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-UHFFFAOYSA-N 0.000 description 1
• ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
• YHUUZKCUQVILTK-UHFFFAOYSA-N 2,3-dimethylpyridin-4-amine Chemical compound CC1=NC=CC(N)=C1C YHUUZKCUQVILTK-UHFFFAOYSA-N 0.000 description 1
• VOYUCTPCAWSYTF-UHFFFAOYSA-N 2,6-dichloro-4-methoxybenzaldehyde Chemical compound COC1=CC(Cl)=C(C=O)C(Cl)=C1 VOYUCTPCAWSYTF-UHFFFAOYSA-N 0.000 description 1
• NFGJQVPDPIGBJE-UHFFFAOYSA-N 2-(4-boronophenyl)acetic acid Chemical compound OB(O)C1=CC=C(CC(O)=O)C=C1 NFGJQVPDPIGBJE-UHFFFAOYSA-N 0.000 description 1
• FFHFPXFZMNEHLG-UHFFFAOYSA-N 2-(bromomethyl)-1,5-dichloro-3-(4-fluorophenyl)benzene Chemical group BrCC1=C(C=C(C=C1Cl)Cl)C1=CC=C(C=C1)F FFHFPXFZMNEHLG-UHFFFAOYSA-N 0.000 description 1
• JWKATABQZWXXTG-UHFFFAOYSA-N 2-[4-[3,5-dichloro-4-[[2-oxo-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-3-yl]methyl]phenyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C(C=C1Cl)=CC(Cl)=C1CC1C(=O)N(C2CC=3C=NNC=3CC2)CC1 JWKATABQZWXXTG-UHFFFAOYSA-N 0.000 description 1
• HTFXWAOSQODIBI-UHFFFAOYSA-N 2-benzyl-1,3-dihydropyrrolo[3,4-c]pyridine Chemical compound C1C2=CC=NC=C2CN1CC1=CC=CC=C1 HTFXWAOSQODIBI-UHFFFAOYSA-N 0.000 description 1
• JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 1
• DDRNQKVAGAWDEE-UHFFFAOYSA-N 2-chlorobutanediamide Chemical compound NC(=O)CC(Cl)C(N)=O DDRNQKVAGAWDEE-UHFFFAOYSA-N 0.000 description 1
• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
• QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
• NFPAXDDXDUDQAC-UHFFFAOYSA-N 3-[(2,4-dichlorophenyl)methyl]-1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one Chemical compound ClC1=CC(Cl)=CC=C1CC1C(=O)N(C2CCC3(CC2)OCCO3)CC1 NFPAXDDXDUDQAC-UHFFFAOYSA-N 0.000 description 1
• DOHLVIFAHSRJMX-UHFFFAOYSA-N 3-[(2,6-dichloro-4-phenylphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound C=1C(Cl)=C(CC2C(N(C3CC=4C=NNC=4CC3)CC2)=O)C(Cl)=CC=1C1=CC=CC=C1 DOHLVIFAHSRJMX-UHFFFAOYSA-N 0.000 description 1
• YWJSYJPDLWHCDS-UHFFFAOYSA-N 3-[(2,6-dichloro-4-propan-2-yloxyphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound ClC1=CC(OC(C)C)=CC(Cl)=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 YWJSYJPDLWHCDS-UHFFFAOYSA-N 0.000 description 1
• WAYCSJAHXIZSPW-UHFFFAOYSA-N 3-[(2,6-dichloro-4-propan-2-yloxyphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one;hydrochloride Chemical compound Cl.ClC1=CC(OC(C)C)=CC(Cl)=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 WAYCSJAHXIZSPW-UHFFFAOYSA-N 0.000 description 1
• APELPEWASRMIJO-UHFFFAOYSA-N 3-[(2-chloro-4-fluorophenyl)methyl]-1-(4-oxocyclohexyl)pyrrolidin-2-one Chemical compound ClC1=CC(F)=CC=C1CC1C(=O)N(C2CCC(=O)CC2)CC1 APELPEWASRMIJO-UHFFFAOYSA-N 0.000 description 1
• CSOGNCRIERHMHB-UHFFFAOYSA-N 3-[(2-chloro-4-methoxyphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound ClC1=CC(OC)=CC=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 CSOGNCRIERHMHB-UHFFFAOYSA-N 0.000 description 1
• VVRZNQIXXXQUDS-UHFFFAOYSA-N 3-[(2-chloro-4-propan-2-yloxyphenyl)methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound ClC1=CC(OC(C)C)=CC=C1CC1C(=O)N(C2CC3=CNN=C3CC2)CC1 VVRZNQIXXXQUDS-UHFFFAOYSA-N 0.000 description 1
• SVNPYNSGUCDTEA-UHFFFAOYSA-N 3-[[2,6-dichloro-4-(4-propan-2-yloxyphenyl)phenyl]methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound C1=CC(OC(C)C)=CC=C1C(C=C1Cl)=CC(Cl)=C1CC1C(=O)N(C2CC=3C=NNC=3CC2)CC1 SVNPYNSGUCDTEA-UHFFFAOYSA-N 0.000 description 1
• ZICFFIINDALPKY-UHFFFAOYSA-N 3-[[2,6-dichloro-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]phenyl]methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound C1CN(C)CCN1C(=O)C1=CC=C(C=2C=C(Cl)C(CC3C(N(C4CC=5C=NNC=5CC4)CC3)=O)=C(Cl)C=2)C=C1 ZICFFIINDALPKY-UHFFFAOYSA-N 0.000 description 1
• YGAKBLFURZWPHN-UHFFFAOYSA-N 3-[[2,6-dichloro-4-[4-(trifluoromethoxy)phenyl]phenyl]methyl]-1-(4,5,6,7-tetrahydro-1h-indazol-5-yl)pyrrolidin-2-one Chemical compound C1=CC(OC(F)(F)F)=CC=C1C(C=C1Cl)=CC(Cl)=C1CC1C(=O)N(C2CC=3C=NNC=3CC2)CC1 YGAKBLFURZWPHN-UHFFFAOYSA-N 0.000 description 1
• HEFLQOGBYFIQAV-UHFFFAOYSA-N 3-[[2-chloro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-1-[3-(dimethylaminomethylidene)-4-oxocyclohexyl]pyrrolidin-2-one Chemical compound C1CC(=O)C(=CN(C)C)CC1N1C(=O)C(CC=2C(=CC(=CC=2)C2=CN(C)N=C2)Cl)CC1 HEFLQOGBYFIQAV-UHFFFAOYSA-N 0.000 description 1
• VQZRLBWPEHFGCD-UHFFFAOYSA-N 3-chloro-4-methylphenol Chemical compound CC1=CC=C(O)C=C1Cl VQZRLBWPEHFGCD-UHFFFAOYSA-N 0.000 description 1
• AQJFATAFTQCRGC-UHFFFAOYSA-N 3-chloro-4-methylphenol Natural products CC1=CC=C(O)C(Cl)=C1 AQJFATAFTQCRGC-UHFFFAOYSA-N 0.000 description 1
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
• DKJBZULWWYRHLT-UHFFFAOYSA-N 4-[3,5-dichloro-4-[[1-[2-[(2-methylpropan-2-yl)oxycarbonyl]-4,5,6,7-tetrahydroindazol-5-yl]-2-oxopyrrolidin-3-yl]methyl]phenyl]benzoic acid Chemical compound C1CC2=NN(C(=O)OC(C)(C)C)C=C2CC1N(C1=O)CCC1CC(C(=C1)Cl)=C(Cl)C=C1C1=CC=C(C(O)=O)C=C1 DKJBZULWWYRHLT-UHFFFAOYSA-N 0.000 description 1
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
• OJOFMLDBXPDXLQ-UHFFFAOYSA-N 4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)NC1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-UHFFFAOYSA-N 0.000 description 1
• DYPSDTOQOSPYOT-UHFFFAOYSA-N 4-bromo-1-(bromomethyl)-2-chlorobenzene Chemical compound ClC1=CC(Br)=CC=C1CBr DYPSDTOQOSPYOT-UHFFFAOYSA-N 0.000 description 1
• WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 description 1
• XXTRGLCPRZQPHJ-UHFFFAOYSA-N 4-hydroxy-2,6-dimethylbenzaldehyde Chemical compound CC1=CC(O)=CC(C)=C1C=O XXTRGLCPRZQPHJ-UHFFFAOYSA-N 0.000 description 1
• MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 1
• VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 1
• WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
• NGHRUBVFDAKWBC-UHFFFAOYSA-N 7-chloroimidazo[1,2-a]pyridine Chemical compound C1=C(Cl)C=CN2C=CN=C21 NGHRUBVFDAKWBC-UHFFFAOYSA-N 0.000 description 1
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
• 102100022734 Acyl carrier protein, mitochondrial Human genes 0.000 description 1
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
• 239000005695 Ammonium acetate Substances 0.000 description 1
• 102000052567 Anaphase-Promoting Complex-Cyclosome Apc1 Subunit Human genes 0.000 description 1
• 102000007592 Apolipoproteins Human genes 0.000 description 1
• 108010071619 Apolipoproteins Proteins 0.000 description 1
• 206010003210 Arteriosclerosis Diseases 0.000 description 1
• UGSHHRVZMJMAEA-UHFFFAOYSA-N B1C(CCC2)CCCC12CC1=CC=CC=C1 Chemical compound B1C(CCC2)CCCC12CC1=CC=CC=C1 UGSHHRVZMJMAEA-UHFFFAOYSA-N 0.000 description 1
• CAHQGWAXKLQREW-UHFFFAOYSA-N Benzal chloride Chemical compound ClC(Cl)C1=CC=CC=C1 CAHQGWAXKLQREW-UHFFFAOYSA-N 0.000 description 1
• 229940123208 Biguanide Drugs 0.000 description 1
• XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
• ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
• 241000283726 Bison Species 0.000 description 1
• 241000283725 Bos Species 0.000 description 1
• 241000283690 Bos taurus Species 0.000 description 1
• 241000282817 Bovidae Species 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
• 241000282472 Canis lupus familiaris Species 0.000 description 1
• 241000283707 Capra Species 0.000 description 1
• 206010007559 Cardiac failure congestive Diseases 0.000 description 1
• 208000006029 Cardiomegaly Diseases 0.000 description 1
• 241000700198 Cavia Species 0.000 description 1
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
• 229920001268 Cholestyramine Polymers 0.000 description 1
• 208000028698 Cognitive impairment Diseases 0.000 description 1
• 229920002911 Colestipol Polymers 0.000 description 1
• 229940126657 Compound 17 Drugs 0.000 description 1
• 241000699800 Cricetinae Species 0.000 description 1
• 101710088194 Dehydrogenase Proteins 0.000 description 1
• 206010070901 Diabetic dyslipidaemia Diseases 0.000 description 1
• 208000010228 Erectile Dysfunction Diseases 0.000 description 1
• PTVSRINJXWDIKP-UHFFFAOYSA-N Ethyl 4-pentenoate Chemical compound CCOC(=O)CCC=C PTVSRINJXWDIKP-UHFFFAOYSA-N 0.000 description 1
• PSCXEUSWZWRCMQ-UHFFFAOYSA-N F[S](F)F Chemical compound F[S](F)F PSCXEUSWZWRCMQ-UHFFFAOYSA-N 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• 230000005526 G1 to G0 transition Effects 0.000 description 1
• 102000001267 GSK3 Human genes 0.000 description 1
• 241000287828 Gallus gallus Species 0.000 description 1
• 208000018522 Gastrointestinal disease Diseases 0.000 description 1
• HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
• 208000010412 Glaucoma Diseases 0.000 description 1
• 206010018404 Glucagonoma Diseases 0.000 description 1
• 102000030595 Glucokinase Human genes 0.000 description 1
• 108010021582 Glucokinase Proteins 0.000 description 1
• 208000002705 Glucose Intolerance Diseases 0.000 description 1
• 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
• 102000015779 HDL Lipoproteins Human genes 0.000 description 1
• 108010010234 HDL Lipoproteins Proteins 0.000 description 1
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
• 101000678845 Homo sapiens Acyl carrier protein, mitochondrial Proteins 0.000 description 1
• 101000611240 Homo sapiens Low molecular weight phosphotyrosine protein phosphatase Proteins 0.000 description 1
• 101000641419 Homo sapiens V-type proton ATPase 16 kDa proteolipid subunit c Proteins 0.000 description 1
• 208000035150 Hypercholesterolemia Diseases 0.000 description 1
• 208000002682 Hyperkalemia Diseases 0.000 description 1
• 208000013016 Hypoglycemia Diseases 0.000 description 1
• 208000019025 Hypokalemia Diseases 0.000 description 1
• 238000004566 IR spectroscopy Methods 0.000 description 1
• 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 1
• 208000031773 Insulin resistance syndrome Diseases 0.000 description 1
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 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 description 1
• 238000006751 Mitsunobu reaction Methods 0.000 description 1
• 241000699666 Mus <mouse, genus> Species 0.000 description 1
• 101000931108 Mus musculus DNA (cytosine-5)-methyltransferase 1 Proteins 0.000 description 1
• 101100354370 Mus musculus Ptprj gene Proteins 0.000 description 1
• RIDIWQOUJJRMHV-UHFFFAOYSA-N O=C1CCC(CC1)NC(O)=O.C(C)(C)(C)OC(C)(C)C Chemical compound O=C1CCC(CC1)NC(O)=O.C(C)(C)(C)OC(C)(C)C RIDIWQOUJJRMHV-UHFFFAOYSA-N 0.000 description 1
• 206010033645 Pancreatitis Diseases 0.000 description 1
• 206010033647 Pancreatitis acute Diseases 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 208000018262 Peripheral vascular disease Diseases 0.000 description 1
• 241000286209 Phasianidae Species 0.000 description 1
• 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 description 1
• 241000288906 Primates Species 0.000 description 1
• 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
• 241000700159 Rattus Species 0.000 description 1
• 102000034527 Retinoid X Receptors Human genes 0.000 description 1
• 108010038912 Retinoid X Receptors Proteins 0.000 description 1
• 241000283984 Rodentia Species 0.000 description 1
• 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 description 1
• 108091006463 SLC25A24 Proteins 0.000 description 1
• 229940124639 Selective inhibitor Drugs 0.000 description 1
• DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
• 229920002472 Starch Polymers 0.000 description 1
• PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 1
• 241000282887 Suidae Species 0.000 description 1
• 239000007983 Tris buffer Substances 0.000 description 1
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
• 208000025865 Ulcer Diseases 0.000 description 1
• 102100034171 V-type proton ATPase 16 kDa proteolipid subunit c Human genes 0.000 description 1
• 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 description 1
• QMVMDYSTJSUDKC-UHFFFAOYSA-N [4-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]boronic acid Chemical compound CC(C)(C)OC(=O)C1=CC=C(B(O)O)C=C1 QMVMDYSTJSUDKC-UHFFFAOYSA-N 0.000 description 1
• VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 1
• RFTKDSUXTLVWOX-UHFFFAOYSA-N [Na].[Na].[Na].O Chemical compound [Na].[Na].[Na].O RFTKDSUXTLVWOX-UHFFFAOYSA-N 0.000 description 1
• WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
• 230000009471 action Effects 0.000 description 1
• 230000004913 activation Effects 0.000 description 1
• 239000004480 active ingredient Substances 0.000 description 1
• 239000011149 active material Substances 0.000 description 1
• 201000003229 acute pancreatitis Diseases 0.000 description 1
• 125000002015 acyclic group Chemical group 0.000 description 1
• 210000000577 adipose tissue Anatomy 0.000 description 1
• 230000032683 aging Effects 0.000 description 1
• 239000000556 agonist Substances 0.000 description 1
• 125000001931 aliphatic group Chemical group 0.000 description 1
• 150000001350 alkyl halides Chemical class 0.000 description 1
• PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
• 150000001413 amino acids Chemical class 0.000 description 1
• 125000003277 amino group Chemical group 0.000 description 1
• 235000019257 ammonium acetate Nutrition 0.000 description 1
• 229940043376 ammonium acetate Drugs 0.000 description 1
• 125000000129 anionic group Chemical group 0.000 description 1
• 230000006909 anti-apoptosis Effects 0.000 description 1
• 230000001142 anti-diarrhea Effects 0.000 description 1
• 239000002518 antifoaming agent Substances 0.000 description 1
• 239000002220 antihypertensive agent Substances 0.000 description 1
• 229940030600 antihypertensive agent Drugs 0.000 description 1
• 210000003433 aortic smooth muscle cell Anatomy 0.000 description 1
• 230000006907 apoptotic process Effects 0.000 description 1
• 208000011775 arteriosclerosis disease Diseases 0.000 description 1
• 150000001543 aryl boronic acids Chemical class 0.000 description 1
• 238000003556 assay Methods 0.000 description 1
• XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
• 230000000923 atherogenic effect Effects 0.000 description 1
• 239000002585 base Substances 0.000 description 1
• 230000009286 beneficial effect Effects 0.000 description 1
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
• FYIZIYCXUSGNLZ-UHFFFAOYSA-N benzyl n-(3-hydroxycyclohexyl)carbamate Chemical compound C1C(O)CCCC1NC(=O)OCC1=CC=CC=C1 FYIZIYCXUSGNLZ-UHFFFAOYSA-N 0.000 description 1
• NDTIOGCPRWWFJC-UHFFFAOYSA-N benzyl n-(3-oxocyclohexyl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCCC(=O)C1 NDTIOGCPRWWFJC-UHFFFAOYSA-N 0.000 description 1
• YXJOJMYMGUHBQG-UHFFFAOYSA-N benzyl n-(4,5,6,7-tetrahydro-1h-indazol-4-yl)carbamate Chemical compound C1CCC=2NN=CC=2C1NC(=O)OCC1=CC=CC=C1 YXJOJMYMGUHBQG-UHFFFAOYSA-N 0.000 description 1
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• 235000010290 biphenyl Nutrition 0.000 description 1
• 239000004305 biphenyl Substances 0.000 description 1
• 230000036772 blood pressure Effects 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• 238000009835 boiling Methods 0.000 description 1
• 229910052796 boron Inorganic materials 0.000 description 1
• 230000031709 bromination Effects 0.000 description 1
• 238000005893 bromination reaction Methods 0.000 description 1
• 239000000872 buffer Substances 0.000 description 1
• 244000309464 bull Species 0.000 description 1
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
• 229910000024 caesium carbonate Inorganic materials 0.000 description 1
• 238000004364 calculation method Methods 0.000 description 1
• 244000309466 calf Species 0.000 description 1
• 125000002837 carbocyclic group Chemical group 0.000 description 1
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
• 230000003683 cardiac damage Effects 0.000 description 1
• 210000000748 cardiovascular system Anatomy 0.000 description 1
• 230000003915 cell function Effects 0.000 description 1
• 238000005119 centrifugation Methods 0.000 description 1
• 239000003610 charcoal Substances 0.000 description 1
• 239000007810 chemical reaction solvent Substances 0.000 description 1
• 235000013330 chicken meat Nutrition 0.000 description 1
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
• 230000001684 chronic effect Effects 0.000 description 1
• 208000020832 chronic kidney disease Diseases 0.000 description 1
• 208000022831 chronic renal failure syndrome Diseases 0.000 description 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 description 1
• 229950009226 ciglitazone Drugs 0.000 description 1
• 238000003776 cleavage reaction Methods 0.000 description 1
• KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
• 229960001214 clofibrate Drugs 0.000 description 1
• 230000015271 coagulation Effects 0.000 description 1
• 238000005345 coagulation Methods 0.000 description 1
• 229960002604 colestipol Drugs 0.000 description 1
• GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
• 230000002860 competitive effect Effects 0.000 description 1
• 229940125773 compound 10 Drugs 0.000 description 1
• 229940125797 compound 12 Drugs 0.000 description 1
• 229940126543 compound 14 Drugs 0.000 description 1
• 229940125758 compound 15 Drugs 0.000 description 1
• 229940125782 compound 2 Drugs 0.000 description 1
• 229940125961 compound 24 Drugs 0.000 description 1
• 229940125846 compound 25 Drugs 0.000 description 1
• 229940126214 compound 3 Drugs 0.000 description 1
• 229940125898 compound 5 Drugs 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
• 239000013058 crude material Substances 0.000 description 1
• 239000002178 crystalline material Substances 0.000 description 1
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
• HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 description 1
• 230000006378 damage Effects 0.000 description 1
• QQKNSPHAFATFNQ-UHFFFAOYSA-N darglitazone Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCC(=O)C(C=C1)=CC=C1CC1SC(=O)NC1=O QQKNSPHAFATFNQ-UHFFFAOYSA-N 0.000 description 1
• 229950006689 darglitazone Drugs 0.000 description 1
• 230000020176 deacylation Effects 0.000 description 1
• 238000005947 deacylation reaction Methods 0.000 description 1
• 230000034994 death Effects 0.000 description 1
• 238000010908 decantation Methods 0.000 description 1
• 230000003111 delayed effect Effects 0.000 description 1
• 239000002274 desiccant Substances 0.000 description 1
• WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
• 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
• 229940043279 diisopropylamine Drugs 0.000 description 1
• 150000002009 diols Chemical class 0.000 description 1
• 238000009826 distribution Methods 0.000 description 1
• 239000002552 dosage form Substances 0.000 description 1
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
• 239000003480 eluent Substances 0.000 description 1
• 229950000269 emiglitate Drugs 0.000 description 1
• 229950002375 englitazone Drugs 0.000 description 1
• 230000002708 enhancing effect Effects 0.000 description 1
• 230000002255 enzymatic effect Effects 0.000 description 1
• 238000006911 enzymatic reaction Methods 0.000 description 1
• 238000001952 enzyme assay Methods 0.000 description 1
• 239000002532 enzyme inhibitor Substances 0.000 description 1
• NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
• NWWORXYTJRPSMC-QKPAOTATSA-N ethyl 4-[2-[(2r,3r,4r,5s)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]ethoxy]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCCN1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)C1 NWWORXYTJRPSMC-QKPAOTATSA-N 0.000 description 1
• MAFQLJCYFMKEJJ-UHFFFAOYSA-N ethyl 4-aminobutanoate Chemical compound CCOC(=O)CCCN MAFQLJCYFMKEJJ-UHFFFAOYSA-N 0.000 description 1
• 238000000605 extraction Methods 0.000 description 1
• 239000004744 fabric Substances 0.000 description 1
• 238000004401 flow injection analysis Methods 0.000 description 1
• 238000012921 fluorescence analysis Methods 0.000 description 1
• 235000013305 food Nutrition 0.000 description 1
• 235000019253 formic acid Nutrition 0.000 description 1
• 230000006870 function Effects 0.000 description 1
• 238000002825 functional assay Methods 0.000 description 1
• 239000007789 gas Substances 0.000 description 1
• 238000004817 gas chromatography Methods 0.000 description 1
• 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
• 230000002496 gastric effect Effects 0.000 description 1
• 229960003627 gemfibrozil Drugs 0.000 description 1
• 239000003365 glass fiber Substances 0.000 description 1
• 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 description 1
• 229960004346 glimepiride Drugs 0.000 description 1
• 230000004110 gluconeogenesis Effects 0.000 description 1
• 230000014101 glucose homeostasis Effects 0.000 description 1
• 125000001475 halogen functional group Chemical group 0.000 description 1
• 244000309465 heifer Species 0.000 description 1
• 230000003284 homeostatic effect Effects 0.000 description 1
• LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 description 1
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 0.000 description 1
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
• 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
• 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
• 208000006575 hypertriglyceridemia Diseases 0.000 description 1
• 229940126904 hypoglycaemic agent Drugs 0.000 description 1
• 230000002218 hypoglycaemic effect Effects 0.000 description 1
• 239000005457 ice water Substances 0.000 description 1
• 150000002462 imidazolines Chemical class 0.000 description 1
• 238000003018 immunoassay Methods 0.000 description 1
• 230000001771 impaired effect Effects 0.000 description 1
• 201000001881 impotence Diseases 0.000 description 1
• 230000006872 improvement Effects 0.000 description 1
• 239000012535 impurity Substances 0.000 description 1
• 238000011534 incubation Methods 0.000 description 1
• 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 1
• 230000006698 induction Effects 0.000 description 1
• 238000002329 infrared spectrum Methods 0.000 description 1
• 239000004615 ingredient Substances 0.000 description 1
• 230000003914 insulin secretion Effects 0.000 description 1
• 230000008991 intestinal motility Effects 0.000 description 1
• 238000007918 intramuscular administration Methods 0.000 description 1
• 238000007912 intraperitoneal administration Methods 0.000 description 1
• 238000001990 intravenous administration Methods 0.000 description 1
• 239000003456 ion exchange resin Substances 0.000 description 1
• 229920003303 ion-exchange polymer Polymers 0.000 description 1
• 208000028867 ischemia Diseases 0.000 description 1
• 230000000302 ischemic effect Effects 0.000 description 1
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
• FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
• ZUBZATZOEPUUQF-UHFFFAOYSA-N isopropylhexane Natural products CCCCCCC(C)C ZUBZATZOEPUUQF-UHFFFAOYSA-N 0.000 description 1
• ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
• 208000001921 latent autoimmune diabetes in adults Diseases 0.000 description 1
• 239000003446 ligand Substances 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 229910052744 lithium Inorganic materials 0.000 description 1
• 239000012280 lithium aluminium hydride Substances 0.000 description 1
• WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
• 235000012054 meals Nutrition 0.000 description 1
• 230000001404 mediated effect Effects 0.000 description 1
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
• IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
• 150000005172 methylbenzenes Chemical class 0.000 description 1
• 229960001110 miglitol Drugs 0.000 description 1
• 229960003365 mitiglinide Drugs 0.000 description 1
• WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
• 238000002156 mixing Methods 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 239000002808 molecular sieve Substances 0.000 description 1
• 208000010125 myocardial infarction Diseases 0.000 description 1
• DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• JJTBQANQYALZLG-UHFFFAOYSA-N n-ethoxy-1-methyl-3-[[3-(trifluoromethyl)phenyl]methoxy]pyrazole-4-carboxamide Chemical compound CCONC(=O)C1=CN(C)N=C1OCC1=CC=CC(C(F)(F)F)=C1 JJTBQANQYALZLG-UHFFFAOYSA-N 0.000 description 1
• 238000006386 neutralization reaction Methods 0.000 description 1
• 150000002825 nitriles Chemical class 0.000 description 1
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
• 238000010606 normalization Methods 0.000 description 1
• 235000015097 nutrients Nutrition 0.000 description 1
• 239000003538 oral antidiabetic agent Substances 0.000 description 1
• 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
• 210000000056 organ Anatomy 0.000 description 1
• 239000003960 organic solvent Substances 0.000 description 1
• 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
• 239000012285 osmium tetroxide Substances 0.000 description 1
• YDCVQGAUCOROHB-UHFFFAOYSA-N oxadiazolidine-4,5-dione Chemical class O=C1NNOC1=O YDCVQGAUCOROHB-UHFFFAOYSA-N 0.000 description 1
• 125000004430 oxygen atom Chemical group O* 0.000 description 1
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
• 230000007310 pathophysiology Effects 0.000 description 1
• OTTYFDRFBJPGRW-UHFFFAOYSA-N pent-2-enoyl chloride Chemical compound CCC=CC(Cl)=O OTTYFDRFBJPGRW-UHFFFAOYSA-N 0.000 description 1
• KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
• 210000002824 peroxisome Anatomy 0.000 description 1
• 230000002085 persistent effect Effects 0.000 description 1
• 239000000825 pharmaceutical preparation Substances 0.000 description 1
• 229940127557 pharmaceutical product Drugs 0.000 description 1
• 150000002989 phenols Chemical class 0.000 description 1
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
• 229960005095 pioglitazone Drugs 0.000 description 1
• VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
• 229960002797 pitavastatin Drugs 0.000 description 1
• 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
• 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
• 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
• 229940068968 polysorbate 80 Drugs 0.000 description 1
• 229920000053 polysorbate 80 Polymers 0.000 description 1
• 230000018656 positive regulation of gluconeogenesis Effects 0.000 description 1
• 230000002980 postoperative effect Effects 0.000 description 1
• 239000003450 potassium channel blocker Substances 0.000 description 1
• 229940125422 potassium channel blocker Drugs 0.000 description 1
• 208000024896 potassium deficiency disease Diseases 0.000 description 1
• 244000144977 poultry Species 0.000 description 1
• 235000013594 poultry meat Nutrition 0.000 description 1
• 229960002965 pravastatin Drugs 0.000 description 1
• 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 description 1
• 238000001556 precipitation Methods 0.000 description 1
• 201000009104 prediabetes syndrome Diseases 0.000 description 1
• 230000035935 pregnancy Effects 0.000 description 1
• 230000002028 premature Effects 0.000 description 1
• 238000009117 preventive therapy Methods 0.000 description 1
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
• FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
• 229960003912 probucol Drugs 0.000 description 1
• 230000008569 process Effects 0.000 description 1
• 230000035755 proliferation Effects 0.000 description 1
• 230000000069 prophylactic effect Effects 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 239000011241 protective layer Substances 0.000 description 1
• 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
• 238000010926 purge Methods 0.000 description 1
• 230000005855 radiation Effects 0.000 description 1
• 150000003254 radicals Chemical class 0.000 description 1
• 229950008257 ragaglitazar Drugs 0.000 description 1
• 239000000376 reactant Substances 0.000 description 1
• 230000035484 reaction time Effects 0.000 description 1
• 102000005962 receptors Human genes 0.000 description 1
• 108020003175 receptors Proteins 0.000 description 1
• 230000009467 reduction Effects 0.000 description 1
• 238000006722 reduction reaction Methods 0.000 description 1
• 230000010410 reperfusion Effects 0.000 description 1
• 230000000717 retained effect Effects 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 238000007363 ring formation reaction Methods 0.000 description 1
• 229960004586 rosiglitazone Drugs 0.000 description 1
• BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
• 229960000672 rosuvastatin Drugs 0.000 description 1
• 102220036542 rs144706057 Human genes 0.000 description 1
• 230000007017 scission Effects 0.000 description 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 229960002855 simvastatin Drugs 0.000 description 1
• 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 description 1
• 210000002460 smooth muscle Anatomy 0.000 description 1
• 229910052708 sodium Inorganic materials 0.000 description 1
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• 235000009518 sodium iodide Nutrition 0.000 description 1
• HQAITFAUVZBHNB-UHFFFAOYSA-N sodium;pentahydrate Chemical compound O.O.O.O.O.[Na] HQAITFAUVZBHNB-UHFFFAOYSA-N 0.000 description 1
• 239000012265 solid product Substances 0.000 description 1
• 239000008107 starch Substances 0.000 description 1
• 235000019698 starch Nutrition 0.000 description 1
• 230000000638 stimulation Effects 0.000 description 1
• 230000035882 stress Effects 0.000 description 1
• 238000010254 subcutaneous injection Methods 0.000 description 1
• 239000007929 subcutaneous injection Substances 0.000 description 1
• DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
• 239000011975 tartaric acid Substances 0.000 description 1
• PMOQFURJWBFKQL-UHFFFAOYSA-N tert-butyl 4-amino-4,5,6,7-tetrahydroindazole-1-carboxylate Chemical compound NC1CCCC2=C1C=NN2C(=O)OC(C)(C)C PMOQFURJWBFKQL-UHFFFAOYSA-N 0.000 description 1
• JYWATPVKXAPTLI-KTKRTIGZSA-N tert-butyl n-[(3z)-3-(dimethylaminomethylidene)-4-oxocyclohexyl]carbamate Chemical compound CN(C)\C=C1\CC(NC(=O)OC(C)(C)C)CCC1=O JYWATPVKXAPTLI-KTKRTIGZSA-N 0.000 description 1
• IYLFKXATVSYTQV-UHFFFAOYSA-N tert-butyl-(chloromethoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCl IYLFKXATVSYTQV-UHFFFAOYSA-N 0.000 description 1
• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
• 238000002560 therapeutic procedure Methods 0.000 description 1
• 150000001467 thiazolidinediones Chemical class 0.000 description 1
• 210000001519 tissue Anatomy 0.000 description 1
• 230000000451 tissue damage Effects 0.000 description 1
• 231100000827 tissue damage Toxicity 0.000 description 1
• 238000004448 titration Methods 0.000 description 1
• 229960002277 tolazamide Drugs 0.000 description 1
• OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
• 238000002054 transplantation Methods 0.000 description 1
• WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
• 150000008648 triflates Chemical class 0.000 description 1
• LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
• GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
• 230000036269 ulceration Effects 0.000 description 1
• 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
• 210000002700 urine Anatomy 0.000 description 1
• 238000003828 vacuum filtration Methods 0.000 description 1
• HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
• 229910052720 vanadium Inorganic materials 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 229960001729 voglibose Drugs 0.000 description 1
• 230000004580 weight loss Effects 0.000 description 1
• 210000004885 white matter Anatomy 0.000 description 1