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

Autor: Arhancet GB; Pfizer Worldwide Medicinal Chemistry, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. graciela.arhancet@novusint.com, Walker DP, Metz S, Fobian YM, Heasley SE, Carter JS, Springer JR, Jones DE, Hayes MJ, Shaffer AF, Jerome GM, Baratta MT, Zweifel B, Moore WM, Masferrer JL, Vazquez ML
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Feb 15; Vol. 23 (4), pp. 1114-9. Date of Electronic Publication: 2012 Dec 06.
DOI: 10.1016/j.bmcl.2012.11.109
Abstrakt: 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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