title: Substituted N-aryl-6-pyrimidinones: a new class of potent, selective, and orally active p38 MAP kinase inhibitors.
abstract: A novel series of highly potent and selective p38 MAP kinase inhibitors was developed originating from a substituted N-aryl-6-pyrimidinone scaffold. SAR studies coupled with in vivo evaluations in rat arthritis model culminated in the identification of 10 with excellent oral efficacy. Compound 10 exhibited a significantly enhanced dissolution rate compared to 1, translating to a high oral bioavailability (>90%) in rat. In animal studies 10 inhibited LPS-stimulated production of tumor necrosis factor-α in a dose-dependent manner and demonstrated robust efficacy comparable to dexamethasone in a rat streptococcal cell wall-induced arthritis model.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. balekudru.devadas@yahoo.com
authors.forename: Balekudru
authors.initials: B
authors.lastname: Devadas
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Selness
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Heather M
authors.initials: HM
authors.lastname: Madsen
authors.forename: Laura D
authors.initials: LD
authors.lastname: Marrufo
authors.forename: Huey
authors.initials: H
authors.lastname: Shieh
authors.forename: Dean M
authors.initials: DM
authors.lastname: Messing
authors.forename: Jerry Z
authors.initials: JZ
authors.lastname: Yang
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Morgan
authors.forename: Gary D
authors.initials: GD
authors.lastname: Anderson
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Webb
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Devraj
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Monahan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D001169:Arthritis, Experimental; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D048051:p38 Mitogen-Activated Protein Kinases