Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase

Maddeboina Krishnaiah; Cheng Hua Jin; Yhun Yhong Sheen; Dae Kee Kim

doi:10.1016/j.bmcl.2015.09.058

Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase

Maddeboina Krishnaiah, Cheng Hua Jin, Yhun Yhong Sheen, Dae Kee Kim

Department of Pharmaceutical Sciences

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

17 Scopus citations

Abstract

To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC₅₀ = 7.68-13.70 nM) and p38α MAP kinase (IC₅₀ = 1240-3370 nM). Among them, 19j inhibited ALK5 with IC₅₀ value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.

Original language	English
Pages (from-to)	5228-5231
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2015.09.058
State	Published - 15 Nov 2015

Bibliographical note

Funding Information:
This work was supported by a Grant from Ministry of Education, Science and Technology , Republic of Korea ( 20100029596 ).

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

ALK5 inhibitor
Cancer
Fibrosis
Kinase assay
TGF-β

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Krishnaiah, M., Jin, C. H., Sheen, Y. Y., & Kim, D. K. (2015). Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase. Bioorganic and Medicinal Chemistry Letters, 25(22), 5228-5231. https://doi.org/10.1016/j.bmcl.2015.09.058

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title = "Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase",

abstract = "To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC50 = 7.68-13.70 nM) and p38α MAP kinase (IC50 = 1240-3370 nM). Among them, 19j inhibited ALK5 with IC50 value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.",

keywords = "ALK5 inhibitor, Cancer, Fibrosis, Kinase assay, TGF-β",

author = "Maddeboina Krishnaiah and Jin, {Cheng Hua} and Sheen, {Yhun Yhong} and Kim, {Dae Kee}",

note = "Funding Information: This work was supported by a Grant from Ministry of Education, Science and Technology , Republic of Korea ( 20100029596 ). Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

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doi = "10.1016/j.bmcl.2015.09.058",

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Krishnaiah, M, Jin, CH, Sheen, YY & Kim, DK 2015, 'Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 22, pp. 5228-5231. https://doi.org/10.1016/j.bmcl.2015.09.058

Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase. / Krishnaiah, Maddeboina; Jin, Cheng Hua; Sheen, Yhun Yhong et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 22, 15.11.2015, p. 5228-5231.

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

TY - JOUR

T1 - Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase

AU - Krishnaiah, Maddeboina

AU - Jin, Cheng Hua

AU - Sheen, Yhun Yhong

AU - Kim, Dae Kee

N1 - Funding Information: This work was supported by a Grant from Ministry of Education, Science and Technology , Republic of Korea ( 20100029596 ). Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/11/15

Y1 - 2015/11/15

N2 - To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC50 = 7.68-13.70 nM) and p38α MAP kinase (IC50 = 1240-3370 nM). Among them, 19j inhibited ALK5 with IC50 value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.

AB - To further optimize a clinical candidate 5 (EW-7197), a series of 5-(3-, 4-, or 5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19a-l have been synthesized and evaluated for their TGF-β type I receptor kinase (ALK5) and p38α MAP kinase inhibitory activity in an enzyme assay. The 5-(5-fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles 19h-l displayed the similar level of potency to that of 5 against both ALK5 (IC50 = 7.68-13.70 nM) and p38α MAP kinase (IC50 = 1240-3370 nM). Among them, 19j inhibited ALK5 with IC50 value of 7.68 nM in a kinase assay and displayed 82% inhibition at 100 nM in a luciferase reporter assay.

KW - ALK5 inhibitor

KW - Cancer

KW - Fibrosis

KW - Kinase assay

KW - TGF-β

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U2 - 10.1016/j.bmcl.2015.09.058

DO - 10.1016/j.bmcl.2015.09.058

M3 - Article

C2 - 26483198

AN - SCOPUS:84945963071

SN - 0960-894X

VL - 25

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ER -

Synthesis and biological evaluation of 5-(fluoro-substituted-6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)imidazoles as inhibitors of transforming growth factor-β type i receptor kinase

Abstract

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