title: Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.
abstract: Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.
authors.affiliation: Pfizer Worldwide Medicinal Chemistry, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. dpwalker@kalexsyn.com
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Walker
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Arhancet
authors.forename: Hwang-Fun
authors.initials: HF
authors.lastname: Lu
authors.forename: Steven E
authors.initials: SE
authors.lastname: Heasley
authors.forename: Sue
authors.initials: S
authors.lastname: Metz
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Kablaoui
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Franco
authors.forename: Cathleen E
authors.initials: CE
authors.lastname: Hanau
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Scholten
authors.forename: John R
authors.initials: JR
authors.lastname: Springer
authors.forename: Yvette M
authors.initials: YM
authors.lastname: Fobian
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Carter
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Shengtian
authors.initials: S
authors.lastname: Yang
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: William M
authors.initials: WM
authors.lastname: Moore
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vazquez
mesh_terms: D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D004791:Enzyme Inhibitors; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases