Synthesis and Biological Evaluation of Quinoline Salicylic Acids As P-Selectin Antagonists

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• 作者：Neelu Kaila ; Kristin Janz ; Silvano DeBernardo ; Patricia W. Bedard ; Raymond T. Camphausen ; Steve Tam ; Desiré ; e H. H. Tsao ; James C. Keith ; Jr. ; Cheryl Nickerson-Nutter ; Adam Shilling ; Ruth Young-
• 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：21 - 39
• 全文大小：304K
• 年卷期：v.50,no.1(January 11, 2007)
• ISSN：1520-4804

文摘

Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along theendothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyteacross cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction ofleukocyte glycoproteins containing active moieties such as sialyl Lewis^x (sLe^x) with P-selectin expressedon endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectinantagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughputscreening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) asantagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLe^x. Throughiterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibitionof dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in therat AIA model of rheumatoid arthritis.