Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase

被引：35

作者：

Eldrup, Anne B. ^{[1
]}

Soleymanzadeh, Fariba ^{[1
]}

Farrow, Neil A. ^{[1
]}

Kukulka, Alison ^{[1
]}

De Lombaert, Stephane ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Dept Med Chem, Ridgefield, CT 06877 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 02期

关键词：

sEH; Soluble epoxide hydrolase; EETs; Epoxide eicosatrienoic acids; 1,3-DISUBSTITUTED UREAS; POTENT INHIBITORS;

D O I：

10.1016/j.bmcl.2009.11.091

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of sEH is hypothesized to lead to an increase in epoxyeicosatrienoic acids resulting in the potentiation of their anti-inflammatory and vasodilatory effects. In an effort to explore sEH inhibition as an avenue for the development of vasodilatory and cardio- or renal-protective agents, a lead identified through high-throughput screening was optimized, guided by the determination of a solid state co-structure with sEH. Replacement of potential toxicophores was followed by optimization of cell-based potency and ADME properties to provide a new class of functionally potent sEH inhibitors with attractive in vitro metabolic profiles and high and sustained plasma exposures after oral administration in the rat. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：571 / 575

页数：5

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