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

Ganesha Rai | Zendy; Netra Joshi | Zendy; Joo Eun Jung | Zendy; Yu Liu | Zendy; Lena Schultz | Zendy; Adam Yasgar | Zendy; Steve Perry | Zendy; Giovanni Diaz | Zendy; Qiangli Zhang | Zendy; Victor Kenyon | Zendy; Ajit Jadhav | Zendy; Anton Simeonov | Zendy; Eng H. Lo | Zendy; Klaus van Leyen | Zendy; David J. Maloney | Zendy; Theodore R. Holman | Zendy

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

Author(s) -

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

Publication year - 2014

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm401915r

Subject(s) - chemistry , pharmacology , in vivo , isozyme , biochemistry , neuroprotection , drug discovery , potency , drug , lipoxygenase , enzyme , in vitro , medicine , biology , microbiology and biotechnology

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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