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

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

doi:10.1016/j.bmc.2010.04.071

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

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

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English
Pages (from-to)	4459-4467
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	18
Issue number	12
DOIs	https://doi.org/10.1016/j.bmc.2010.04.071
State	Published - 15 Jun 2010

Bibliographical note

Funding Information:
This work was supported by a grant from Ministry of Commerce, Industry and Energy, Korea ( 10027900 ).

Keywords

ALK5 inhibitor
Cell-based luciferase reporter assays
TGF-β

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10.1016/j.bmc.2010.04.071

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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. (2010). Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors. Bioorganic and Medicinal Chemistry, 18(12), 4459-4467. https://doi.org/10.1016/j.bmc.2010.04.071

@article{415a034822f94bf7ae977117c1cd598c,

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",

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.",

keywords = "ALK5 inhibitor, Cell-based luciferase reporter assays, TGF-β",

author = "Kim, \{Dae Kee\} and Lee, \{Yeon Im\} and Lee, \{Yeon Woo\} and Dewang, \{Purushottam M.\} and Sheen, \{Yhun Yhong\} and Kim, \{Yeo Woon\} and Park, \{Hyun Ju\} and Jakyung Yoo and Lee, \{Ho Soon\} and Kim, \{Yong Kook\}",

note = "Funding Information: This work was supported by a grant from Ministry of Commerce, Industry and Energy, Korea ( 10027900 ). ",

year = "2010",

month = jun,

day = "15",

doi = "10.1016/j.bmc.2010.04.071",

language = "English",

volume = "18",

pages = "4459--4467",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd.",

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Kim, DK, Lee, YI, Lee, YW, Dewang, PM, Sheen, YY, Kim, YW, Park, HJ, Yoo, J, Lee, HS & Kim, YK 2010, 'Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors', Bioorganic and Medicinal Chemistry, vol. 18, no. 12, pp. 4459-4467. https://doi.org/10.1016/j.bmc.2010.04.071

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T1 - Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

AU - Kim, Dae Kee

AU - Lee, Yeon Im

AU - Lee, Yeon Woo

AU - Dewang, Purushottam M.

AU - Sheen, Yhun Yhong

AU - Kim, Yeo Woon

AU - Park, Hyun Ju

AU - Yoo, Jakyung

AU - Lee, Ho Soon

AU - Kim, Yong Kook

N1 - Funding Information: This work was supported by a grant from Ministry of Commerce, Industry and Energy, Korea ( 10027900 ).

PY - 2010/6/15

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AB - 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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ER -

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

Abstract

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Keywords

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