title: Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.
abstract: Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.
authors.affiliation: Department of Chemistry, Locus Pharmaceuticals, Inc., Four Valley Square, 512 Township Line Rd, Blue Bell, PA 19422, USA.
authors.forename: Enrique L
authors.initials: EL
authors.lastname: Michelotti
authors.forename: Kristofer K
authors.initials: KK
authors.lastname: Moffett
authors.forename: Duyan
authors.initials: D
authors.lastname: Nguyen
authors.forename: Martha J
authors.initials: MJ
authors.lastname: Kelly
authors.forename: Rupa
authors.initials: R
authors.lastname: Shetty
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Chai
authors.forename: Katrina
authors.initials: K
authors.lastname: Northrop
authors.forename: Variketta
authors.initials: V
authors.lastname: Namboodiri
authors.forename: Brandon
authors.initials: B
authors.lastname: Campbell
authors.forename: Gary A
authors.initials: GA
authors.lastname: Flynn
authors.forename: Ted
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Frank P
authors.initials: FP
authors.lastname: Hollinger
authors.forename: Marina
authors.initials: M
authors.lastname: Bukhtiyarova
authors.forename: Eric B
authors.initials: EB
authors.lastname: Springman
authors.forename: Michael
authors.initials: M
authors.lastname: Karpusas
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004987:Ethers / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D004987:Ethers; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14