Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase
Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase
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DOI：
10.1016/j.bmcl.2009.11.091
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发表时间：
2010-01-15
影响因子：
2.7
通讯作者：
De Lombaert, Stephane
中科院分区：
文献类型：
--
作者：
Eldrup, Anne B.;Soleymanzadeh, Fariba;De Lombaert, Stephane
据推测，抑制 sEH 会导致环氧二十碳三烯酸增加，从而增强其抗炎和血管舒张作用。为了探索 sEH 抑制作为开发血管舒张剂和心脏或肾脏保护剂的途径，在确定与 sEH 的固态共结构的指导下，优化了通过高通量筛选鉴定的先导化合物。替换潜在的毒载体后，优化基于细胞的效力和 ADME 特性，以提供一类新型功能有效的 sEH 抑制剂，其具有有吸引力的体外代谢特征，并且在大鼠口服给药后具有高且持续的血浆暴露量。 (C) 2009 Elsevier Ltd. 保留所有权利。
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.