Discovery of 2-[1-(4-chlorophenyl) cyclopropyl]-3-hydroxy-8-(trifluoromethyl) quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved …

…, V Clerin, N Sushkova, B Tchernychev…

Index: Huang, Adrian; Moretto, Alessandro; Janz, Kristin; Lowe, Michael; Bedard, Patricia W.; Tam, Steve; Di, Li; Clerin, Valerie; Sushkova, Natalia; Tchernychev, Boris; Tsao, Desiree H. H.; Keith Jr., James C.; Shaw, Gray D.; Schaub, Robert G.; Wang, Qin; Kaila, Neelu Journal of Medicinal Chemistry, 2010 , vol. 53, # 16 p. 6003 - 6017

Full Text: HTML

Citation Number: 14

Abstract

Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound ...