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

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

42 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 - https://www.scopus.com/pages/publications/80052927702

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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