Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors |
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Authors: | Dae-Kee Kim Yeon-Im Lee Yeon Woo Lee Purushottam M Dewang Yhun Yhong Sheen Yeo Woon Kim Hyun-Ju Park Jakyung Yoo Ho Soon Lee Yong-Kook Kim |
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Institution: | 1. College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea;2. College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea;3. In2Gen Co., Ltd, 608 Daerung Posttower II Building, 182-13 Guro-dong, Guro-gu, Seoul 152-050, Republic of Korea |
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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. |
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