title: Discovery of PH-797804, a highly selective and potent inhibitor of p38 MAP kinase.
abstract: The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, United States. shaun.selness@gmail.com
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Selness
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Devraj
authors.forename: Balekudru
authors.initials: B
authors.lastname: Devadas
authors.forename: John K
authors.initials: JK
authors.lastname: Walker
authors.forename: Terri L
authors.initials: TL
authors.lastname: Boehm
authors.forename: Richard C
authors.initials: RC
authors.lastname: Durley
authors.forename: Huey
authors.initials: H
authors.lastname: Shieh
authors.forename: Li
authors.initials: L
authors.lastname: Xing
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
authors.forename: Dean
authors.initials: D
authors.lastname: Messing
authors.forename: Jerry
authors.initials: J
authors.lastname: Yang
authors.forename: Michael K
authors.initials: MK
authors.lastname: Mao
authors.forename: Gopi
authors.initials: G
authors.lastname: Yalamanchili
authors.forename: Richard
authors.initials: R
authors.lastname: Vonder Embse
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hirsch
authors.forename: Matthew
authors.initials: M
authors.lastname: Saabye
authors.forename: Sheri
authors.initials: S
authors.lastname: Bonar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Webb
authors.forename: Gary
authors.initials: G
authors.lastname: Anderson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Monahan
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D011728:Pyridones; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; C542398:PH 797804; D011728:Pyridones; D011753:Pyrones; D048051:p38 Mitogen-Activated Protein Kinases