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

Microsomal prostaglandin E2 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...

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Published in:Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (4), p.1120-1126
Main Authors: Walker, Daniel P., Arhancet, Graciela B., Lu, Hwang-Fun, Heasley, Steven E., Metz, Sue, Kablaoui, Natasha M., Franco, Francisco M., Hanau, Cathleen E., Scholten, Jeffrey A., Springer, John R., Fobian, Yvette M., Carter, Jeffrey S., Xing, Li, Yang, Shengtian, Shaffer, Alexander F., Jerome, Gina M., Baratta, Michael T., Moore, William M., Vazquez, Michael L.
Format: Article
Language:English
Subjects:
Acyl glucuronide
Benzoxazole
Benzoxazoles - chemical synthesis
Benzoxazoles - chemistry
Benzoxazoles - pharmacology
chemistry
Conformation
Conformational analysis
Cyclohexane
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Inflammation
Intramolecular Oxidoreductases - antagonists & inhibitors
Intramolecular Oxidoreductases - chemistry
Intramolecular Oxidoreductases - metabolism
Models, Molecular
Molecular Conformation
mPGES-1
Pain
Prostaglandin E2
Prostaglandin-E synthase
Prostaglandin-E Synthases
prostaglandins
Solubility
Structure-Activity Relationship
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Summary:Microsomal prostaglandin E2 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.11.107