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.
Graciela B Arhancet  1 ,  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
Affiliations
  • 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.

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