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J Med Chem. 2014 May 22;57(10):4035-48. doi: 10.1021/jm401915r. Epub 2014 May 13.

Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies.

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Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , Charlestown, Massachusetts 02129, United States.


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.

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