The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme–ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α in...

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Bibliographic Details
Published in:	ACS medicinal chemistry letters Vol. 2; no. 10; pp. 758 - 763
Main Authors:	Duffy, John P, Harrington, Edmund M, Salituro, Francesco G, Cochran, John E, Green, Jeremy, Gao, Huai, Bemis, Guy W, Evindar, Ghotas, Galullo, Vincent P, Ford, Pamella J, Germann, Ursula A, Wilson, Keith P, Bellon, Steven F, Chen, Guanging, Taslimi, Paul, Jones, Peter, Huang, Cassey, Pazhanisamy, S, Wang, Yow-Ming, Murcko, Mark A, Su, Michael S.S
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 13-10-2011
Subjects:	Letter p38 inhibitor inflammatory diseases VX-745
Online Access:	Get full text
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Summary:	The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme–ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1948-5875 1948-5875
DOI:	10.1021/ml2001455