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

John P Duffy, Edmund M Harrington, Francesco G Salituro, John E Cochran, Jeremy Green, Huai Gao, Guy W Bemis, Ghotas Evindar, Vincent P Galullo, Pamella J Ford, Ursula A Germann, Keith P Wilson, Steven F Bellon, etc.

ACS Med Chem Lett. 2011 Jul 28;2(10):758-63.

PMID: 24900264

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP209410468	VX-745		209410-46-8	Price