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

  • ACS Med Chem Lett. 2011 Jul 28;2(10):758-63. doi: 10.1021/ml2001455.
John P Duffy  1 ,  Edmund M Harrington  1 ,  Francesco G Salituro  1 ,  John E Cochran  1 ,  Jeremy Green  1 ,  Huai Gao  1 ,  Guy W Bemis  1 ,  Ghotas Evindar  1 ,  Vincent P Galullo  1 ,  Pamella J Ford  1 ,  Ursula A Germann  1 ,  Keith P Wilson  1 ,  Steven F Bellon  1 ,  Guanging Chen  1 ,  Paul Taslimi  1 ,  Peter Jones  1 ,  Cassey Huang  1 ,  S Pazhanisamy  1 ,  Yow-Ming Wang  1 ,  Mark A Murcko  1 ,  Michael S S Su  1
Affiliations
  • 1. Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
PMID: 24900264 DOI: 10.1021/ml2001455
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.

Keywords
VX-745; inflammatory diseases; p38 inhibitor.
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