Discovery of Potent and Selective Inhibitors of Human Platelet-Type 12- Lipoxygenase

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• 作者：Victor Kenyon ; Ganesha Rai ; Ajit Jadhav ; Lena Schultz ; Michelle Armstrong ; J. Brian Jameson ; II ; Steven Perry ; Netra Joshi ; James M. Bougie ; William Leister ; David A. Taylor-Fishwick ; Jerry L. Nadler ; Michael Holinstat ; Anton Simeonov ; David J. Maloney ; Theodore R. Holman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 11, 2011
• 年：2011
• 卷：54
• 期：15
• 页码：5485-5497
• 全文大小：1034K
• 年卷期：v.54,no.15(August 11, 2011)
• ISSN：1520-4804

文摘

We report the discovery of novel small molecule inhibitors of platelet-type 12-human lipoxygenase, which display nanomolar activity against the purified enzyme, using a quantitative high-throughput screen (qHTS) on a library of 153607 compounds. These compounds also exhibit excellent specificity, >50-fold selectivity vs the paralogues, 5-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity vs ovine cyclooxygenase-1 and human cyclooxygenase-2. Kinetic experiments indicate this chemotype is a noncompetitive inhibitor that does not reduce the active site iron. Moreover, chiral HPLC separation of two of the racemic lead molecules revealed a strong preference for the (鈭?-enantiomers (IC₅₀ of 0.43 卤 0.04 and 0.38 卤 0.05 渭M) compared to the (+)-enantiomers (IC₅₀ of >25 渭M for both), indicating a fine degree of selectivity in the active site due to chiral geometry. In addition, these compounds demonstrate efficacy in cellular models, which underscores their relevance to disease modification.