Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies
| Autor: | Theodore R. Holman, Eng H. Lo, Netra Joshi, Ganesha Rai, Qiangli Zhang, Adam Yasgar, Joo Eun Jung, David J. Maloney, Giovanni Diaz, Anton Simeonov, Victor Kenyon, Yu Liu, Klaus van Leyen, Ajit Jadhav, Lena Schultz, Steve Perry |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Reticulocytes
Pharmacology Arachidonate 12-Lipoxygenase Isozyme Article Lipoxygenase Mice Structure-Activity Relationship In vivo Drug Discovery medicine Animals Arachidonate 15-Lipoxygenase Humans Lipoxygenase Inhibitors Stroke IC50 biology Chemistry Drug discovery Glutamate receptor medicine.disease High-Throughput Screening Assays Toxicity biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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