- Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation
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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.
- 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.
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p. 1114 - 1119
(2013/03/14)
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