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.
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
[reaction: see text] An enantioselective synthetic method for alpha-alkylserines by the phase-transfer catalytic alkylation of 2-phenyl-2-oxazoline-4-carbonylcamphorsultam (4a) was developed. The phase-transfer catalytic alpha-alkylation of 4a using P2-Et at -78 degrees C gave alpha-alkylation (75 to approximately 99%, 90 to approximately 97% de), which could be easily hydrolyzed to alpha-alkylserines.
