Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

Cheng Hua Jin; Maddeboina Krishnaiah; Domalapally Sreenu; Vura Bala Subrahmanyam; Kota Sudhakar Rao; Annaji Venkata Nagendra Mohan; Chul Yong Park; Jee Yeon Son; Yhun Yhong Sheen; Dae Kee Kim

doi:10.1016/j.bmcl.2011.08.064

Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

Cheng Hua Jin, Maddeboina Krishnaiah, Domalapally Sreenu, Vura Bala Subrahmanyam, Kota Sudhakar Rao, Annaji Venkata Nagendra Mohan, Chul Yong Park, Jee Yeon Son, Yhun Yhong Sheen, Dae Kee Kim

Department of Pharmaceutical Sciences

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38 Scopus citations

Abstract

A series of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4triazolo[1,5- apyridin-6-yl)pyrazoles 14a-ae, 16a, 16b, and 21a-c has been prepared and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 4-([1,2,4triazolo[1,5-apyridin-6-yl)- N-(4-methoxyphenyl)-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carbothioamide (14n) inhibited ALK5 phosphorylation with IC ₅₀ value of 0.57 nM and showed 94% inhibition at 100 nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.

Original language	English
Pages (from-to)	6049-6053
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	20
DOIs	https://doi.org/10.1016/j.bmcl.2011.08.064
State	Published - 15 Oct 2011

Bibliographical note

Funding Information:
This work was supported by RP-Grant 2010 of Ewha Womans University .

Keywords

ALK5 inhibitor
Cancer
Cell-based luciferase reporter assay
Fibrosis
Kinase assay
TGF-β

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10.1016/j.bmcl.2011.08.064

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Jin, C. H., Krishnaiah, M., Sreenu, D., Subrahmanyam, V. B., Rao, K. S., Mohan, A. V. N., Park, C. Y., Son, J. Y., Sheen, Y. Y., & Kim, D. K. (2011). Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 21(20), 6049-6053. https://doi.org/10.1016/j.bmcl.2011.08.064

@article{403bad3ef23249a3bf0be9869f940127,

title = "Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors",

abstract = "A series of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4triazolo[1,5- apyridin-6-yl)pyrazoles 14a-ae, 16a, 16b, and 21a-c has been prepared and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 4-([1,2,4triazolo[1,5-apyridin-6-yl)- N-(4-methoxyphenyl)-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carbothioamide (14n) inhibited ALK5 phosphorylation with IC 50 value of 0.57 nM and showed 94% inhibition at 100 nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.",

keywords = "ALK5 inhibitor, Cancer, Cell-based luciferase reporter assay, Fibrosis, Kinase assay, TGF-β",

author = "Jin, {Cheng Hua} and Maddeboina Krishnaiah and Domalapally Sreenu and Subrahmanyam, {Vura Bala} and Rao, {Kota Sudhakar} and Mohan, {Annaji Venkata Nagendra} and Park, {Chul Yong} and Son, {Jee Yeon} and Sheen, {Yhun Yhong} and Kim, {Dae Kee}",

note = "Funding Information: This work was supported by RP-Grant 2010 of Ewha Womans University .",

year = "2011",

month = oct,

day = "15",

doi = "10.1016/j.bmcl.2011.08.064",

language = "English",

volume = "21",

pages = "6049--6053",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd.",

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Jin, CH, Krishnaiah, M, Sreenu, D, Subrahmanyam, VB, Rao, KS, Mohan, AVN, Park, CY, Son, JY, Sheen, YY & Kim, DK 2011, 'Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 20, pp. 6049-6053. https://doi.org/10.1016/j.bmcl.2011.08.064

Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors. / Jin, Cheng Hua; Krishnaiah, Maddeboina; Sreenu, Domalapally et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 20, 15.10.2011, p. 6049-6053.

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

TY - JOUR

T1 - Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

AU - Jin, Cheng Hua

AU - Krishnaiah, Maddeboina

AU - Sreenu, Domalapally

AU - Subrahmanyam, Vura Bala

AU - Rao, Kota Sudhakar

AU - Mohan, Annaji Venkata Nagendra

AU - Park, Chul Yong

AU - Son, Jee Yeon

AU - Sheen, Yhun Yhong

AU - Kim, Dae Kee

N1 - Funding Information: This work was supported by RP-Grant 2010 of Ewha Womans University .

PY - 2011/10/15

Y1 - 2011/10/15

N2 - A series of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4triazolo[1,5- apyridin-6-yl)pyrazoles 14a-ae, 16a, 16b, and 21a-c has been prepared and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 4-([1,2,4triazolo[1,5-apyridin-6-yl)- N-(4-methoxyphenyl)-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carbothioamide (14n) inhibited ALK5 phosphorylation with IC 50 value of 0.57 nM and showed 94% inhibition at 100 nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.

AB - A series of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4triazolo[1,5- apyridin-6-yl)pyrazoles 14a-ae, 16a, 16b, and 21a-c has been prepared and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 4-([1,2,4triazolo[1,5-apyridin-6-yl)- N-(4-methoxyphenyl)-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carbothioamide (14n) inhibited ALK5 phosphorylation with IC 50 value of 0.57 nM and showed 94% inhibition at 100 nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.

KW - ALK5 inhibitor

KW - Cancer

KW - Cell-based luciferase reporter assay

KW - Fibrosis

KW - Kinase assay

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=80052927702&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2011.08.064

DO - 10.1016/j.bmcl.2011.08.064

M3 - Article

C2 - 21911290

AN - SCOPUS:80052927702

SN - 0960-894X

VL - 21

SP - 6049

EP - 6053

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 20

ER -

Jin CH, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Mohan AVN et al. Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors. Bioorganic and Medicinal Chemistry Letters. 2011 Oct 15;21(20):6049-6053. doi: 10.1016/j.bmcl.2011.08.064

Synthesis and biological evaluation of 1-substituted-3-(6-methylpyridin-2- yl)-4-([1,2,4triazolo[1,5-apyridin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors

Abstract

Bibliographical note

Keywords

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