1067187-64-7Relevant articles and documents
Discovery of 2-[1-(4-Chlorophenyl)cyclopropyl]-3-hydroxy-8- (trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury
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
supporting information; experimental part, p. 6003 - 6017 (2010/11/19)
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 with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the α position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.
