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Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Feb 15; Vol. 23 (4), pp. 1114-9. Date of Electronic Publication: 2012 Dec 06. - Publication Year :
- 2013
-
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.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Drug Discovery
Humans
Inflammation enzymology
Intramolecular Oxidoreductases metabolism
Prostaglandin-E Synthases
Structure-Activity Relationship
Anti-Inflammatory Agents chemistry
Anti-Inflammatory Agents pharmacology
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Inflammation drug therapy
Intramolecular Oxidoreductases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 23
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 23260349
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.11.109