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

Graciela B Arhancet; Daniel P Walker; Sue Metz; Yvette M Fobian; Steven E Heasley; Jeffrey S Carter; John R Springer; Darin E Jones; Michael J Hayes; Alexander F Shaffer; Gina M Jerome; Michael T Baratta; Ben Zweifel; William M Moore; Jaime L Masferrer; Michael L Vazquez

doi:10.1016/j.bmcl.2012.11.109

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

Bioorg Med Chem Lett. 2013 Feb 15;23(4):1114-9. doi: 10.1016/j.bmcl.2012.11.109. Epub 2012 Dec 6.

Authors

Graciela B Arhancet¹, Daniel P Walker, Sue Metz, Yvette M Fobian, Steven E Heasley, Jeffrey S Carter, John R Springer, Darin E Jones, Michael J Hayes, Alexander F Shaffer, Gina M Jerome, Michael T Baratta, Ben Zweifel, William M Moore, Jaime L Masferrer, Michael L Vazquez

Affiliation

¹ Pfizer Worldwide Medicinal Chemistry, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. [email protected]

PMID: 23260349
DOI: 10.1016/j.bmcl.2012.11.109

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.

MeSH terms

Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / pharmacology*
Drug Discovery
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Inflammation / drug therapy*
Inflammation / enzymology
Intramolecular Oxidoreductases / antagonists & inhibitors*
Intramolecular Oxidoreductases / metabolism
Prostaglandin-E Synthases
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents
Enzyme Inhibitors
Intramolecular Oxidoreductases
PTGES protein, human
Prostaglandin-E Synthases