Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.

Autor: Walker DP; Pfizer Worldwide Medicinal Chemistry, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. dpwalker@kalexsyn.com, Arhancet GB, Lu HF, Heasley SE, Metz S, Kablaoui NM, Franco FM, Hanau CE, Scholten JA, Springer JR, Fobian YM, Carter JS, Xing L, Yang S, Shaffer AF, Jerome GM, Baratta MT, Moore WM, Vazquez ML
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Feb 15; Vol. 23 (4), pp. 1120-6. Date of Electronic Publication: 2012 Dec 12.
DOI: 10.1016/j.bmcl.2012.11.107
Abstrakt: 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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