Discovery of Potent and Selective Inhibitors of Human Reticulocyte 15-Lipoxygenase-1

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• 作者：Ganesha Rai ; Victor Kenyon ; Ajit Jadhav ; Lena Schultz ; Michelle Armstrong ; J. Brian Jameson ; II ; Eric Hoobler ; William Leister ; Anton Simeonov ; Theodore R. Holman ; David J. Maloney
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 28, 2010
• 年：2010
• 卷：53
• 期：20
• 页码：7392-7404
• 全文大小：1098K
• 年卷期：v.53,no.20(October 28, 2010)
• ISSN：1520-4804

文摘

There are a variety of lipoxygenases in the human body (hLO), each having a distinct role in cellular biology. Human reticulocyte 15-lipoxygenase-1 (15-hLO-1), which catalyzes the dioxygenation of 1,4-cis,cis-pentadiene-containing polyunsaturated fatty acids, is implicated in a number of diseases including cancer, atherosclerosis, and neurodegenerative conditions. Despite the potential therapeutic relevance of this target, few inhibitors have been reported that are both potent and selective. To this end, we have employed a quantitative high-throughput (qHTS) screen against 74000 small molecules in search of reticulocyte 15-hLO-1 selective inhibitors. This screen led to the discovery of a novel chemotype for 15-hLO-1 inhibition, which displays nM potency and is >7500-fold selective against the related isozymes, 5-hLO, platelet 12-hLO, epithelial 15-hLO-2, ovine cyclooxygenase-1, and human cyclooxygenase-2. In addition, kinetic experiments were performed which indicate that this class of inhibitor is tight binding, reversible, and appears not to reduce the active-site ferric ion.