Document Report Card

ID: ALA3259653

Journal: J Med Chem

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

Authors: Rai G, Joshi N, Jung JE, Liu Y, Schultz L, Yasgar A, Perry S, Diaz G, Zhang Q, Kenyon V, Jadhav A, Simeonov A, Lo EH, van Leyen K, Maloney DJ, Holman TR.

Abstract: 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.

CiteXplore: 24684213

DOI: 10.1021/jm401915r