bimosiamose and Venous-Thrombosis

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 alpha 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.

Topics: Administration, Oral; Animals; Caco-2 Cells; Carotid Artery Injuries; Cell Membrane Permeability; Dogs; Drug Stability; Humans; Hydroxyquinolines; Leukocyte Rolling; Macaca fascicularis; Mice; Mice, Inbred C57BL; Microsomes, Liver; Models, Molecular; P-Selectin; Papio; Rats; Rats, Sprague-Dawley; Salicylates; Solubility; Structure-Activity Relationship; Venous Thrombosis