53657-72-0Relevant articles and documents
Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies
Rai, 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.
supporting information, p. 4035 - 4048 (2014/06/09)
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 (IC 50 = 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.
