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

Pfizer Worldwide Medicinal Chemistry, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. Electronic address: .
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 12/2012; 23(4). DOI: 10.1016/j.bmcl.2012.11.107
Source: PubMed


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.

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