Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

被引：83

作者：

Rai, Ganesha ^{[2
]}

Joshi, Netra ^{[3
]}

Jung, Joo Eun ^{[1
]}

Liu, Yu ^{[1
]}

Schultz, Lena ^{[2
]}

Yasgar, Adam ^{[2
]}

Perry, Steve ^{[3
]}

Diaz, Giovanni ^{[3
]}

Zhang, Qiangli ^{[3
]}

Kenyon, Victor ^{[3
]}

Jadhav, Ajit ^{[2
]}

Simeonov, Anton ^{[2
]}

Lo, Eng H. ^{[1
]}

van Leyen, Klaus ^{[1
]}

Maloney, David J. ^{[2
]}

Holman, Theodore R. ^{[3
]}

机构：

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA 02129 USA

[2] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA

[3] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 10期

基金：

美国国家卫生研究院;

关键词：

SPONGE-DERIVED TERPENOIDS; 5-LIPOXYGENASE INHIBITION; HUMAN; 15-LIPOXYGENASE; 12/15; LIPOXYGENASE; OXIDATIVE STRESS; ARTERIAL-WALL; 12-LIPOXYGENASE; DISCOVERY; APOPTOSIS; ZILEUTON;

D O I：

10.1021/jm401915r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4035 / 4048

页数：14

共 41 条

[41] Discovery two potent and new inhibitors of 15-lipoxygenase: (E)-3-((3,4-dihydroxybenzylidene) amino)-7-hydroxy-2H-chromen-2-one and (E)-O-(4-(((7-hydroxy-2-oxo-2H-chromen-3-yl) imino)methine) phenyl)dimethylcarbamothioate
Carolina Nuñez
Nicole Morales
Olimpo García-Beltran
Carolina Mascayano
Angelica Fierro
Medicinal Chemistry Research, 2017, 26 : 2707 - 2717

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