title: Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase.
abstract: A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity 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.selness@gmail.com
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Selness
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
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Devraj
authors.forename: Dean
authors.initials: D
authors.lastname: Messing
authors.forename: John F
authors.initials: JF
authors.lastname: Schindler
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; D004195:Disease Models, Animal; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D011728:Pyridones; D011743:Pyrimidines; D048051:p38 Mitogen-Activated Protein Kinases; C464966:VX-745