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Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

Title
Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors
Authors
Kim D.-K.Lee Y.-I.Lee Y.W.Dewang P.M.Sheen Y.Y.Kim Y.W.Park H.-J.Yoo J.Lee H.S.Kim Y.-K.
Ewha Authors
신윤용김대기
SCOPUS Author ID
신윤용scopus; 김대기scopus
Issue Date
2010
Journal Title
Bioorganic and Medicinal Chemistry
ISSN
0968-0896JCR Link
Citation
vol. 18, no. 12, pp. 4459 - 4467
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 IC50 values of 0.026 and 0.034 μM, respectively. In a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct, 18 displayed 66% inhibition at 0.05 μM, 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. © 2010 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2010.04.071
Appears in Collections:
약학대학 > 약학과 > Journal papers
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