The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor.

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Duffy JP, Harrington EM, Salituro FG, Cochran JE, Green J, Gao H, Bemis GW, Evindar G, Galullo VP, Ford PJ, Germann UA, Wilson KP, Bellon SF, Chen G, Taslimi P, Jones P, Huang C, Pazhanisamy S, Wang YM, Murcko MA, Su MS

The Discovery of VX-745: A Novel and Selective p38alpha Kinase Inhibitor.

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

PubMed ID

24900264 [ View in PubMed

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Abstract

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38alpha 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 p38alpha 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-o ne (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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Neflamapimod	Mitogen-activated protein kinase 14	Protein	Humans	Unknown	Not Available	Details