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

Paradigms and Technologies
Therapeutic Approaches
Medicinal Chemistry


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.


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


  • Animals
  • Arachidonate 12-Lipoxygenase/ metabolism
  • Arachidonate 15-Lipoxygenase/ metabolism
  • High-Throughput Screening Assays
  • Humans
  • Lipoxygenase Inhibitors/ pharmacology
  • Lipoxygenase Inhibitors/ therapeutic use
  • Mice
  • Reticulocytes/ enzymology
  • Stroke/ drug therapy
  • Structure-Activity Relationship

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