title: Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase.
abstract: The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. shaun.r.selness@pfizer.com
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Selness
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Devraj
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Monahan
authors.forename: Terri L
authors.initials: TL
authors.lastname: Boehm
authors.forename: John K
authors.initials: JK
authors.lastname: Walker
authors.forename: Balekudru
authors.initials: B
authors.lastname: Devadas
authors.forename: Richard C
authors.initials: RC
authors.lastname: Durley
authors.forename: Ravi
authors.initials: R
authors.lastname: Kurumbail
authors.forename: Huey
authors.initials: H
authors.lastname: Shieh
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Michael
authors.initials: M
authors.lastname: Hepperle
authors.forename: Paul V
authors.initials: PV
authors.lastname: Rucker
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Jerome
authors.forename: Alan G
authors.initials: AG
authors.lastname: Benson
authors.forename: Laura D
authors.initials: LD
authors.lastname: Marrufo
authors.forename: Heather M
authors.initials: HM
authors.lastname: Madsen
authors.forename: Jeff
authors.initials: J
authors.lastname: Hitchcock
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Owen
authors.forename: Lance
authors.initials: L
authors.lastname: Christie
authors.forename: Michele A
authors.initials: MA
authors.lastname: Promo
authors.forename: Brian S
authors.initials: BS
authors.lastname: Hickory
authors.forename: Edgardo
authors.initials: E
authors.lastname: Alvira
authors.forename: Win
authors.initials: W
authors.lastname: Naing
authors.forename: Radhika
authors.initials: R
authors.lastname: Blevis-Bal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases