ABSTRACT
A series of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles, 7a-c, 11a-h, and 16a-h has been synthesised and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Incorporation of a quinoxalin-6-yl moiety and a methylene linker at the 4- and 2-position of the imidazole ring, respectively, and a m-CONH2 substituent in the phenyl ring generated a highly potent and selective ALK5 inhibitor 11e. Docking model of ALK5 in complex with 11e showed that it fitted well in the ATP-binding pocket with favourable interactions.
Subject(s)
Imidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , Caco-2 Cells , Cell Line , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Receptor, Transforming Growth Factor-beta Type I/metabolism , Structure-Activity RelationshipABSTRACT
A series of 2-pyridyl-substituted pyrazoles (16a-d, 17, 18, and 28a-e) and imidazoles (22 and 23) has been synthesized and evaluated for their ALK5 inhibitory activity in cell-based luciferase reporter assays. Among them, 3-(3-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-pyrazole-1-carbothioamido)benzamide (28c) showed 96% and 93% inhibition at 0.1 microM in luciferase reporter assays using HaCaT cells transiently transfected with p3TP-luc reporter construct and ARE-luc reporter construct, respectively.
Subject(s)
Imidazoles/chemical synthesis , Imidazoles/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Cell Line , Humans , Receptor, Transforming Growth Factor-beta Type IABSTRACT
A series of 4(5)-(6-methylpyridin-2-yl)imidazoles 16-19 and -pyrazoles 22-29, 33, and 34 have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in cell-based luciferase reporter assays. The 6-quinolinyl imidazole analogs 16 and 18 inhibited ALK5 phosphorylation with IC(50) values of 0.026 and 0.034 microM, respectively. In a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct, 18 displayed 66% inhibition at 0.05 microM, while competitor compounds 2 and 3 showed 44% inhibition. The binding mode of 18 generated by flexible docking studies with ALK5:18 complex shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions.
Subject(s)
Imidazoles/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Binding Sites , Catalytic Domain , Cell Line , Computer Simulation , Cytochrome P-450 Enzyme System/metabolism , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolismABSTRACT
A series of benzenesulfonamide-substituted 4-(6-alkylpyridin-2-yl)-5-(quinoxalin-6-yl)imidazoles have been synthesized and evaluated for their ALK5 inhibitory activity in cell-based luciferase reporter assays. Among them, 4-[5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-ylmethyl]benzenesulfonamide and 4-[5-(6-ethylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-ylmethyl]benzenesulfonamide showed more than 90% inhibition at 0.5 microM in a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct, but inhibited p38alpha MAP kinase activity only 11 and 8% at a concentration of 10 microM, respectively.
Subject(s)
Imidazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Cell Line , Humans , Imidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor, Transforming Growth Factor-beta Type I , Structure-Activity Relationship , Sulfonamides , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , BenzenesulfonamidesABSTRACT
A series of trisubstituted imidazole derivatives containing a 4-fluorophenyl group, a pyrimidine ring, and a CN- or CONH(2)-substituted benzyl moiety have been synthesized and evaluated for p38alpha MAP kinase inhibitory activity. Among them, compounds 22c, 27b, and 28b inhibited p38alpha MAP kinase with IC(50) values 27.6, 28, and 31 nM, respectively.
Subject(s)
Chemistry, Pharmaceutical/methods , Imidazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/chemistry , Anti-Inflammatory Agents/pharmacology , Drug Design , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , MAP Kinase Signaling System , Models, Chemical , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Recombinant Proteins/chemistry , Structure-Activity RelationshipABSTRACT
Protein tyrosine phosphatase (PTP) is the family of enzymes that are key players in cellular signal transduction system and perturbation in their functioning is implicated in many disease-states. Diverse chemical compounds are being synthesized and evaluated as PTP inhibitors. This review presents a brief account of various enzymes of the PTP family and their inhibitors. Peculiar features of these enzymes and their roles in various diseases are summarized along with important inhibitors developed in recent years.
