title: Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.
abstract: Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies.
authors.affiliation: Pfizer Worldwide Medicinal Chemistry, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. graciela.arhancet@novusint.com
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Arhancet
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walker
authors.forename: Sue
authors.initials: S
authors.lastname: Metz
authors.forename: Yvette M
authors.initials: YM
authors.lastname: Fobian
authors.forename: Steven E
authors.initials: SE
authors.lastname: Heasley
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Carter
authors.forename: John R
authors.initials: JR
authors.lastname: Springer
authors.forename: Darin E
authors.initials: DE
authors.lastname: Jones
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hayes
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Shaffer
authors.forename: Gina M
authors.initials: GM
authors.lastname: Jerome
authors.forename: Michael T
authors.initials: MT
authors.lastname: Baratta
authors.forename: Ben
authors.initials: B
authors.lastname: Zweifel
authors.forename: William M
authors.initials: WM
authors.lastname: Moore
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Masferrer
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vazquez
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases