JP2019524831A5 - - Google Patents
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- Publication number
- JP2019524831A5 JP2019524831A5 JP2019508858A JP2019508858A JP2019524831A5 JP 2019524831 A5 JP2019524831 A5 JP 2019524831A5 JP 2019508858 A JP2019508858 A JP 2019508858A JP 2019508858 A JP2019508858 A JP 2019508858A JP 2019524831 A5 JP2019524831 A5 JP 2019524831A5
- Authority
- JP
- Japan
- Prior art keywords
- pyridin
- carboxamide
- oxy
- pharmaceutically acceptable
- ethoxypyridin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000003112 inhibitor Substances 0.000 claims 21
- 150000001875 compounds Chemical class 0.000 claims 18
- -1 5-((3-Ethoxy-5-fluoropyridin-2-yl) oxy) pyridin-3-yl Chemical group 0.000 claims 16
- 150000003839 salts Chemical class 0.000 claims 16
- 239000000203 mixture Substances 0.000 claims 12
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims 9
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims 7
- 208000019425 cirrhosis of liver Diseases 0.000 claims 6
- 239000008177 pharmaceutical agent Substances 0.000 claims 5
- 206010016654 Fibrosis Diseases 0.000 claims 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims 4
- 230000007882 cirrhosis Effects 0.000 claims 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims 4
- 208000004930 Fatty Liver Diseases 0.000 claims 3
- 238000010276 construction Methods 0.000 claims 3
- 229940075993 receptor modulator Drugs 0.000 claims 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- DFNKRIPGDXQUEM-QFIPXVFZSA-N 2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-[(3S)-3-(hydroxymethyl)oxolan-3-yl]pyrimidine-5-carboxamide Chemical compound C(C)OC=1C(=NC=CC=1)OC=1C=C(C=NC=1)C1=NC=C(C=N1)C(=O)N[C@]1(COCC1)CO DFNKRIPGDXQUEM-QFIPXVFZSA-N 0.000 claims 2
- UKBQFBRPXKGJPY-INIZCTEOSA-N 2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-[(3S)-oxolan-3-yl]pyrimidine-5-carboxamide Chemical compound C(C)OC=1C(=NC=CC=1)OC=1C=C(C=NC=1)C1=NC=C(C=N1)C(=O)N[C@@H]1COCC1 UKBQFBRPXKGJPY-INIZCTEOSA-N 0.000 claims 2
- 102000002148 Diacylglycerol O-acyltransferase Human genes 0.000 claims 2
- 108010001348 Diacylglycerol O-acyltransferase Proteins 0.000 claims 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 claims 2
- 102100025353 G-protein coupled bile acid receptor 1 Human genes 0.000 claims 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims 2
- 206010019708 Hepatic steatosis Diseases 0.000 claims 2
- 101000857733 Homo sapiens G-protein coupled bile acid receptor 1 Proteins 0.000 claims 2
- 102100030643 Hydroxycarboxylic acid receptor 2 Human genes 0.000 claims 2
- 102000004877 Insulin Human genes 0.000 claims 2
- 108090001061 Insulin Proteins 0.000 claims 2
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 claims 2
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 claims 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims 2
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 claims 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 claims 2
- 239000012190 activator Substances 0.000 claims 2
- 239000000654 additive Substances 0.000 claims 2
- 230000000996 additive effect Effects 0.000 claims 2
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims 2
- 239000005557 antagonist Substances 0.000 claims 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 2
- 229940125708 antidiabetic agent Drugs 0.000 claims 2
- 239000003472 antidiabetic agent Substances 0.000 claims 2
- 235000012000 cholesterol Nutrition 0.000 claims 2
- 239000013078 crystal Substances 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 208000010706 fatty liver disease Diseases 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 229940124828 glucokinase activator Drugs 0.000 claims 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 229940125396 insulin Drugs 0.000 claims 2
- 150000002632 lipids Chemical class 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 238000000634 powder X-ray diffraction Methods 0.000 claims 2
- 230000005855 radiation Effects 0.000 claims 2
- 231100000240 steatosis hepatitis Toxicity 0.000 claims 2
- 125000001424 substituent group Chemical group 0.000 claims 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims 1
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 claims 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims 1
- KHXPARUTHKQJQB-UHFFFAOYSA-N 2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-(2-methylsulfonylpropan-2-yl)pyrimidine-5-carboxamide Chemical compound CCOc1cccnc1Oc1cncc(c1)-c1ncc(cn1)C(=O)NC(C)(C)S(C)(=O)=O KHXPARUTHKQJQB-UHFFFAOYSA-N 0.000 claims 1
- UKBQFBRPXKGJPY-MRXNPFEDSA-N 2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-[(3R)-oxolan-3-yl]pyrimidine-5-carboxamide Chemical compound C(C)OC=1C(=NC=CC=1)OC=1C=C(C=NC=1)C1=NC=C(C=N1)C(=O)N[C@H]1COCC1 UKBQFBRPXKGJPY-MRXNPFEDSA-N 0.000 claims 1
- ROJNYKZWTOHRNU-UHFFFAOYSA-N 2-chloro-4,5-difluoro-n-[[2-methoxy-5-(methylcarbamoylamino)phenyl]carbamoyl]benzamide Chemical compound CNC(=O)NC1=CC=C(OC)C(NC(=O)NC(=O)C=2C(=CC(F)=C(F)C=2)Cl)=C1 ROJNYKZWTOHRNU-UHFFFAOYSA-N 0.000 claims 1
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 claims 1
- DGENZVKCTGIDRZ-UHFFFAOYSA-N 3-[4-[(3-phenoxyphenyl)methylamino]phenyl]propanoic acid Chemical compound C1=CC(CCC(=O)O)=CC=C1NCC1=CC=CC(OC=2C=CC=CC=2)=C1 DGENZVKCTGIDRZ-UHFFFAOYSA-N 0.000 claims 1
- ZVQDMWKMNDSSSS-UHFFFAOYSA-N 3-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-triazine-6-carboxamide Chemical compound C(C)OC=1C(=NC=CC=1)OC=1C=C(C=NC=1)C=1N=NC(=CN=1)C(=O)NC(CO)(C)C ZVQDMWKMNDSSSS-UHFFFAOYSA-N 0.000 claims 1
- IZDYJXOIVYNSFU-AWEZNQCLSA-N 3-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]-N-[(3S)-oxolan-3-yl]-1,2,4-triazine-6-carboxamide Chemical compound C(C)OC=1C(=NC=CC=1)OC=1C=C(C=NC=1)C=1N=NC(=CN=1)C(=O)N[C@@H]1COCC1 IZDYJXOIVYNSFU-AWEZNQCLSA-N 0.000 claims 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims 1
- MPLLLQUZNJSVTK-UHFFFAOYSA-N 5-[3-[4-[2-(4-fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1CCCC(C=C1)=CC=C1OCCC1=CC=C(F)C=C1 MPLLLQUZNJSVTK-UHFFFAOYSA-N 0.000 claims 1
- 229940123324 Acyltransferase inhibitor Drugs 0.000 claims 1
- 102100031786 Adiponectin Human genes 0.000 claims 1
- 108010076365 Adiponectin Proteins 0.000 claims 1
- 102000016912 Aldehyde Reductase Human genes 0.000 claims 1
- 108010053754 Aldehyde reductase Proteins 0.000 claims 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims 1
- 101710171801 Alpha-amylase inhibitor Proteins 0.000 claims 1
- 229940123208 Biguanide Drugs 0.000 claims 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 claims 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 claims 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims 1
- 102000002666 Carnitine O-palmitoyltransferase Human genes 0.000 claims 1
- 108010018424 Carnitine O-palmitoyltransferase Proteins 0.000 claims 1
- 229910016523 CuKa Inorganic materials 0.000 claims 1
- 108010011459 Exenatide Proteins 0.000 claims 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 claims 1
- 108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 claims 1
- 229940127405 Fatty Acid Synthetase Inhibitors Drugs 0.000 claims 1
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- 108010087894 Fatty acid desaturases Proteins 0.000 claims 1
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- 108090000376 Fibroblast growth factor 21 Proteins 0.000 claims 1
- 102100040133 Free fatty acid receptor 2 Human genes 0.000 claims 1
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- 102000027487 Fructose-Bisphosphatase Human genes 0.000 claims 1
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 claims 1
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- 229940125827 GPR40 agonist Drugs 0.000 claims 1
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- 108010046569 Galectins Proteins 0.000 claims 1
- 108010072051 Glatiramer Acetate Proteins 0.000 claims 1
- 108010063919 Glucagon Receptors Proteins 0.000 claims 1
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- 101000890668 Homo sapiens Free fatty acid receptor 2 Proteins 0.000 claims 1
- 101000890662 Homo sapiens Free fatty acid receptor 3 Proteins 0.000 claims 1
- 101000890672 Homo sapiens Free fatty acid receptor 4 Proteins 0.000 claims 1
- 101001009541 Homo sapiens G-protein coupled receptor 39 Proteins 0.000 claims 1
- 101000996752 Homo sapiens Glucose-dependent insulinotropic receptor Proteins 0.000 claims 1
- 101000843810 Homo sapiens Hydroxycarboxylic acid receptor 1 Proteins 0.000 claims 1
- 101000843809 Homo sapiens Hydroxycarboxylic acid receptor 2 Proteins 0.000 claims 1
- 101001059984 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 4 Proteins 0.000 claims 1
- 101001121539 Homo sapiens P2Y purinoceptor 14 Proteins 0.000 claims 1
- 101100463125 Homo sapiens PDK4 gene Proteins 0.000 claims 1
- 101000994669 Homo sapiens Potassium voltage-gated channel subfamily A member 3 Proteins 0.000 claims 1
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 claims 1
- 101001051777 Homo sapiens Protein kinase C alpha type Proteins 0.000 claims 1
- 101001051767 Homo sapiens Protein kinase C beta type Proteins 0.000 claims 1
- 101001026864 Homo sapiens Protein kinase C gamma type Proteins 0.000 claims 1
- 101000695838 Homo sapiens Receptor-type tyrosine-protein phosphatase U Proteins 0.000 claims 1
- 101001093899 Homo sapiens Retinoic acid receptor RXR-alpha Proteins 0.000 claims 1
- 101001117143 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial Proteins 0.000 claims 1
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- 101710125793 Hydroxycarboxylic acid receptor 2 Proteins 0.000 claims 1
- 229940122199 Insulin secretagogue Drugs 0.000 claims 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims 1
- 108010019598 Liraglutide Proteins 0.000 claims 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims 1
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- ABMPUDBHFWWYQO-UHFFFAOYSA-N N-(1,4-dihydroxy-2-methylbutan-2-yl)-2-[5-(3-ethoxypyridin-2-yl)oxypyridin-3-yl]pyrimidine-5-carboxamide Chemical compound CCOc1cccnc1Oc1cncc(c1)-c1ncc(cn1)C(=O)NC(C)(CO)CCO ABMPUDBHFWWYQO-UHFFFAOYSA-N 0.000 claims 1
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- 229940124754 PPAR-alpha/gamma agonist Drugs 0.000 claims 1
- 230000010705 Peroxisome Proliferator-activated Receptor Activity Effects 0.000 claims 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 claims 1
- 102100034355 Potassium voltage-gated channel subfamily A member 3 Human genes 0.000 claims 1
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 claims 1
- 102000001708 Protein Isoforms Human genes 0.000 claims 1
- 108010029485 Protein Isoforms Proteins 0.000 claims 1
- 108090000315 Protein Kinase C Proteins 0.000 claims 1
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- 102100024923 Protein kinase C beta type Human genes 0.000 claims 1
- 102100037314 Protein kinase C gamma type Human genes 0.000 claims 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
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