1283496-07-0Relevant academic research and scientific papers
INHIBITORS OF HUMAN 12/15-LIPOXYGENASE
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Paragraph 00255, (2015/03/13)
A systematic screening has revealed a family of compounds that exhibit inhibitory effects on 12/15-lipoxygenase. Accordingly, the present invention relates to the use of these compounds for the inhibition of 12/15-lipoxygenase and for the treatment of a condition involving 12/15-lipoxygenase. Exemplary conditions include, but are not limited to, stroke, periventricular leukomalacia, cardiac arrest with resuscitation, atherosclerosis, Parkinson's disease, Alzheimer's disease, and breast cancer.
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.
