title: The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor.
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.
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Duffy
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Edmund M
authors.initials: EM
authors.lastname: Harrington
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Cochran
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Green
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Huai
authors.initials: H
authors.lastname: Gao
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Guy W
authors.initials: GW
authors.lastname: Bemis
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Ghotas
authors.initials: G
authors.lastname: Evindar
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Galullo
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Pamella J
authors.initials: PJ
authors.lastname: Ford
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Ursula A
authors.initials: UA
authors.lastname: Germann
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Wilson
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bellon
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Guanging
authors.initials: G
authors.lastname: Chen
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Taslimi
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Jones
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Cassey
authors.initials: C
authors.lastname: Huang
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: S
authors.initials: S
authors.lastname: Pazhanisamy
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Yow-Ming
authors.initials: YM
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Murcko
authors.affiliation: Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.
authors.forename: Michael S S
authors.initials: MS
authors.lastname: Su
keywords: VX-745; inflammatory diseases; p38 inhibitor