1427581-44-9Relevant academic research and scientific papers
Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation
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.
, p. 1114 - 1119 (2013/03/14)
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.
