title: Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-beta type 1 receptor kinase inhibitors.
abstract: 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.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seodaemun-gu, Seoul 120-750, Republic of Korea. dkkim@ewha.ac.kr
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.forename: Yeon-Im
authors.initials: YI
authors.lastname: Lee
authors.forename: Yeon Woo
authors.initials: YW
authors.lastname: Lee
authors.forename: Purushottam M
authors.initials: PM
authors.lastname: Dewang
authors.forename: Yhun Yhong
authors.initials: YY
authors.lastname: Sheen
authors.forename: Yeo Woon
authors.initials: YW
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.forename: Ho Soon
authors.initials: HS
authors.lastname: Lee
authors.forename: Yong-Kook
authors.initials: YK
authors.lastname: Kim
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D018125:Receptors, Transforming Growth Factor beta; C029899:imidazole; D003577:Cytochrome P-450 Enzyme System; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human