Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies.
Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies.
复制标题
DOI：
10.1021/jm401915r
复制
发表时间：
2014-05-22
影响因子：
7.3
通讯作者：
Holman TR
中科院分区：
文献类型：
--
作者：
Rai G;Joshi N;Jung JE;Liu Y;Schultz L;Yasgar A;Perry S;Diaz G;Zhang Q;Kenyon V;Jadhav A;Simeonov A;Lo EH;van Leyen K;Maloney DJ;Holman TR
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.
登录
查看更多内容
DOI：
10.1111/j.1742-1241.2007.01320.x
发表时间：
2007-04-01
影响因子：
2.6
作者：
Berger, W.;De Chandt, M. T. M.;Cairns, C. B.
通讯作者：
Cairns, C. B.
影响因子：
5.1
作者：
Amagata, T;Whitman, S;Holman, TR
通讯作者：
Holman, TR
影响因子：
--
作者：
HUSSAIN, H;SHORNICK, LP;HOLTZMAN, MJ
通讯作者：
HOLTZMAN, MJ
影响因子：
7.3
作者：
DIANA, GD;TREASURYWALA, AM;DUTKO, FJ
通讯作者：
DUTKO, FJ
影响因子：
7.3
作者：
Kenyon, Victor;Rai, Ganesha;Holman, Theodore R.
通讯作者：
Holman, Theodore R.