Design, synthesis, and biological activity of 1,3-Disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase of increased water solubility
Design, synthesis, and biological activity of 1,3-Disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase of increased water solubility
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DOI：
10.1021/jm030514j
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发表时间：
2004-04-08
影响因子：
7.3
通讯作者：
Hammock, BD
中科院分区：
文献类型：
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作者：
Kim, IH;Morisseau, C;Hammock, BD
可溶性环氧化物水解酶（sEH）参与内源性化学介质的代谢，这些介质在血压调节和炎症中起重要作用。1，3-二取代脲是有效的sEH抑制剂，在体外和体内都有活性。然而，它们在水或脂质中的溶解性差降低了它们的体内功效，并使它们难以配制。为了改善这些物理性质，将极性官能团纳入烷基链之一的影响进行了评估，其抑制剂效力，水溶性，辛醇/水分配系数（log P），和熔点。当极性官能团从中心脲羰基引入至少5个原子（类似于7.5埃）时，没有观察到抑制效力的损失。此外，分别对于小鼠和人sEH，存在距离脲羰基至少11个原子的极性基团不会改变抑制剂效力。所得化合物具有更好的水溶性，并且通常比非官能化亲脂脲具有更低的log P值和熔点。这些性质将使化合物更具有生物利用度，并且更易溶于水基或油基制剂中。
The soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in blood pressure regulation and inflammation. 1,3-Disubstituted ureas are potent inhibitors of sEH that are active both in vitro and in vivo. However, their poor solubility in either water or lipid reduces their in vivo efficacy and makes them difficult to formulate. To improve these physical properties, the effect of incorporating polar functional groups into one of the alkyl chains was evaluated on their inhibitor potencies, water solubility, octanol/water partition coefficients (log P), and melting points. No loss of inhibition potency was observed when a polar functional group was incorporated at least five atoms (similar to7.5 Angstrom) from the central urea carbonyl. In addition, the presence of a polar group at least 11 atoms away from the urea carbonyl group for the mouse and human sEHs, respectively, did not alter the inhibitor potency. The resulting compounds have better water solubility and generally lower log P values and melting points than nonfanctionalized liphophilic ureas. These properties will make the compounds more bioavailable and more soluble in either water- or oil-based formulations.