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

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• 作者：Adrian Huang ; Alessandro Moretto ; Kristin Janz ; Michael Lowe ; Patricia W. Bedard ; Steve Tam ; Li Di ; Valerie Clerin ; Natalia Sushkova ; Boris Tchernychev ; Desiree H. H. Tsao ; James C. Keith ; Jr. ; Gray D
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 26, 2010
• 年：2010
• 卷：53
• 期：16
• 页码：6003-6017
• 全文大小：1219K
• 年卷期：v.53,no.16(August 26, 2010)
• ISSN：1520-4804

文摘

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.