The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor
ACS Medicinal Chemistry Letters2011Vol. 2(10), pp. 758–763
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John P. Duffy, Edmund Harrington, Francesco G. Salituro, John E. Cochran, Jeremy Green, Huai Gao, Guy W. Bemis, Ghotas Evindar, Vincent Galullo, Pamella J. Ford, Ursula A. Germann, Keith P. Wilson, Steven F. Bellon, Guanging Chen, Paul Taslimi, Peter Lloyd Jones, Cassey Huang, S. Pazhanisamy, Yow‐Ming Wang, Mark A. Murcko, Michael Su
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.
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