2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-B1 and activin A signalling

Rudy Ciayadi; Mahesh Potdar; Kelly L. Walton; Craig A. Harrison; Geoffrey F. Kelso; Simon J. Harris; Milton T. W. Hearn

doi:10.1016/j.bmcl.2010.12.120

2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-B1 and activin A signalling

Rudy Ciayadi, Mahesh Potdar, Kelly L. Walton, Craig A. Harrison, Geoffrey F. Kelso, Simon J. Harris, Milton T. W. Hearn

Research output: Contribution to journal › Letter › Other › peer-review

12 Citations (Scopus)

Abstract

Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.

Original language	English
Pages (from-to)	5642-5645
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2010.12.120
Publication status	Published - 2011

Keywords

Transforming growth factor-β
activin A
low molecular weight inhibitors
structure-activity relationships
ATP-competitive ALK4/ALK5 inhibitors

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10.1016/j.bmcl.2010.12.120

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title = "2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-B1 and activin A signalling",

abstract = "Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.",

keywords = "Transforming growth factor-β, activin A, low molecular weight inhibitors, structure-activity relationships, ATP-competitive ALK4/ALK5 inhibitors",

author = "Rudy Ciayadi and Mahesh Potdar and Walton, {Kelly L.} and Harrison, {Craig A.} and Kelso, {Geoffrey F.} and Harris, {Simon J.} and Hearn, {Milton T. W.}",

year = "2011",

doi = "10.1016/j.bmcl.2010.12.120",

language = "English",

volume = "21",

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journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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T1 - 2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-B1 and activin A signalling

AU - Ciayadi, Rudy

AU - Potdar, Mahesh

AU - Walton, Kelly L.

AU - Harrison, Craig A.

AU - Kelso, Geoffrey F.

AU - Harris, Simon J.

AU - Hearn, Milton T. W.

PY - 2011

Y1 - 2011

N2 - Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.

AB - Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.

KW - Transforming growth factor-β

KW - activin A

KW - low molecular weight inhibitors

KW - structure-activity relationships

KW - ATP-competitive ALK4/ALK5 inhibitors

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U2 - 10.1016/j.bmcl.2010.12.120

DO - 10.1016/j.bmcl.2010.12.120

M3 - Letter

SN - 0960-894X

VL - 21

SP - 5642

EP - 5645

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-B1 and activin A signalling

Abstract

Keywords

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