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

35 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",

publisher = "Elsevier Masson s.r.l.",

number = "9",

}

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

UR - https://www.scopus.com/pages/publications/80052951712

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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