Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation

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, selec...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (4), p.1114-1119
Main Authors: Arhancet, Graciela B., Walker, Daniel P., Metz, Sue, Fobian, Yvette M., Heasley, Steven E., Carter, Jeffrey S., Springer, John R., Jones, Darin E., Hayes, Michael J., Shaffer, Alexander F., Jerome, Gina M., Baratta, Michael T., Zweifel, Ben, Moore, William M., Masferrer, Jaime L., Vazquez, Michael L.
Format: Article
Language:English
Subjects:
air
anti-inflammatory agents
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
Antiinflammatory agents
arachidonic acid
Benzoxazole
Clinical candidate
clinical trials
Drug Discovery
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
guinea pigs
Humans
Inflammation
Inflammation - drug therapy
Inflammation - enzymology
Intramolecular Oxidoreductases - antagonists & inhibitors
Intramolecular Oxidoreductases - metabolism
m-PGES-1
PF-4693627
pharmacokinetics
Prostaglandin-E Synthases
prostaglandins
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.11.109