Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

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• 作者：Ganesha Rai ; Netra Joshi ; Joo Eun Jung ; Yu Liu ; Lena Schultz ; Adam Yasgar ; Steve Perry ; Giovanni Diaz ; Qiangli Zhang ; Victor Kenyon ; Ajit Jadhav ; Anton Simeonov ; Eng H. Lo ; Klaus van Leyen ; David J. Maloney ; Theodore R. Holman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4035-4048
• 全文大小：601K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC₅₀ = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.