2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H]quinoline-4-carboxylic Acid (PSI-697): Identification of a Clinical Candidate from the Quinoline Salicylic Acid Series of P-Selectin Anta

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• 作者：Neelu Kaila ; Kristin Janz ; Adrian Huang ; Alessandro Moretto ; Silvano DeBernardo ; Patricia W. Bedard ; Steve Tam ; Valerie Clerin ; James C. Keith ; Jr. ; Desiré ; e H. H. Tsao ; Natalia Sushkova ; Gray D
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：January 11, 2007
• 年：2007
• 卷：50
• 期：1
• 页码：40 - 64
• 全文大小：597K
• 年卷期：v.50,no.1(January 11, 2007)
• ISSN：1520-4804

文摘

P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequentlyleads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues.P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectinantagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening andsubsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we reportthe continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinolinesalicylic acids. These compounds have improved pharmacokinetic properties, and a number of them haveshown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697),is currently in clinical development for the treatment of atherothrombotic vascular events.