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

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

doi:10.1016/j.ejmech.2011.05.063

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

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

Department of Pharmaceutical Sciences

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

34 Scopus citations

Abstract

A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl) pyrazoles 14a-d, 15a-d, 17a, 17b, 18a-d, 19a, and 19b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 2-[3-(6-methylpyridin-2-yl)-4- (quinoxalin-6-yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) inhibited ALK5 phosphorylation with an IC ₅₀ value of 0.013 μM and showed 80% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.

Original language	English
Pages (from-to)	3917-3925
Number of pages	9
Journal	European Journal of Medicinal Chemistry
Volume	46
Issue number	9
DOIs	https://doi.org/10.1016/j.ejmech.2011.05.063
State	Published - Sep 2011

Bibliographical note

Funding Information:
This work was supported by RP-Grant 2009 of Ewha Womans University and a grant from Ministry of Education, Science and Technology, Korea ( 20100029596 ).

Keywords

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

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10.1016/j.ejmech.2011.05.063

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Jin, C. H., Sreenu, D., Krishnaiah, M., Subrahmanyam, V. B., Rao, K. S., Nagendra Mohan, A. V., Park, C. Y., Son, J. Y., Son, D. H., Park, H. J., Sheen, Y. Y., & Kim, D. K. (2011). Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin- 2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors. European Journal of Medicinal Chemistry, 46(9), 3917-3925. https://doi.org/10.1016/j.ejmech.2011.05.063

@article{0b7d6575fe0548368b5ab466e9e35690,

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

abstract = "A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl) pyrazoles 14a-d, 15a-d, 17a, 17b, 18a-d, 19a, and 19b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 2-[3-(6-methylpyridin-2-yl)-4- (quinoxalin-6-yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) inhibited ALK5 phosphorylation with an IC 50 value of 0.013 μM and showed 80% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.",

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

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

note = "Funding Information: This work was supported by RP-Grant 2009 of Ewha Womans University and a grant from Ministry of Education, Science and Technology, Korea ( 20100029596 ).",

year = "2011",

month = sep,

doi = "10.1016/j.ejmech.2011.05.063",

language = "English",

volume = "46",

pages = "3917--3925",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

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Jin, CH, Sreenu, D, Krishnaiah, M, Subrahmanyam, VB, Rao, KS, Nagendra Mohan, AV, Park, CY, Son, JY, Son, DH, Park, HJ, Sheen, YY & Kim, DK 2011, 'Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin- 2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors', European Journal of Medicinal Chemistry, vol. 46, no. 9, pp. 3917-3925. https://doi.org/10.1016/j.ejmech.2011.05.063

Synthesis and biological evaluation of 1-substituted-3(5)-(6-methylpyridin- 2-yl)-4-(quinoxalin-6-yl)pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors. / Jin, Cheng Hua; Sreenu, Domalapally; Krishnaiah, Maddeboina et al.
In: European Journal of Medicinal Chemistry, Vol. 46, No. 9, 09.2011, p. 3917-3925.

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

TY - JOUR

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

AU - Jin, Cheng Hua

AU - Sreenu, Domalapally

AU - Krishnaiah, Maddeboina

AU - Subrahmanyam, Vura Bala

AU - Rao, Kota Sudhakar

AU - Nagendra Mohan, Annaji Venkata

AU - Park, Chul Yong

AU - Son, Jee Yeon

AU - Son, Do Hyun

AU - Park, Hyun Ju

AU - Sheen, Yhun Yhong

AU - Kim, Dae Kee

N1 - Funding Information: This work was supported by RP-Grant 2009 of Ewha Womans University and a grant from Ministry of Education, Science and Technology, Korea ( 20100029596 ).

PY - 2011/9

Y1 - 2011/9

N2 - A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl) pyrazoles 14a-d, 15a-d, 17a, 17b, 18a-d, 19a, and 19b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 2-[3-(6-methylpyridin-2-yl)-4- (quinoxalin-6-yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) inhibited ALK5 phosphorylation with an IC 50 value of 0.013 μM and showed 80% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.

AB - A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl) pyrazoles 14a-d, 15a-d, 17a, 17b, 18a-d, 19a, and 19b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 2-[3-(6-methylpyridin-2-yl)-4- (quinoxalin-6-yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) inhibited ALK5 phosphorylation with an IC 50 value of 0.013 μM and showed 80% inhibition at 0.1 μM 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 - Docking

KW - Fibrosis

KW - Kinase assay

KW - TGF-β

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U2 - 10.1016/j.ejmech.2011.05.063

DO - 10.1016/j.ejmech.2011.05.063

M3 - Article

C2 - 21696866

AN - SCOPUS:80052951712

SN - 0223-5234

VL - 46

SP - 3917

EP - 3925

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 9

ER -

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

Abstract

Bibliographical note

Keywords

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