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. 2011 Jul 28;2(10):758-63.
doi: 10.1021/ml2001455. eCollection 2011 Oct 13.

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

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

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

John P Duffy et al. ACS Med Chem Lett. .

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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Figures

Figure 1
Figure 1
Inhibitors of p38 MAP kinase.
Figure 2
Figure 2
Structure of screening hit, as reported by vendor.
Scheme 1
Scheme 1
Figure 3
Figure 3
Structure of 3 bound to p38.
See this image and copyright information in PMC

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