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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • 12-15-lipoxygenase
  • Lipoxygenase Inhibitors
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase