2. Academic Validation
  3. The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor

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

Affiliation

  • 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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