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首页> 外文期刊>Journal of Medicinal Chemistry >Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility
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Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility

机译：改善水溶性的酰胺基可溶性环氧水解酶抑制剂的优化

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Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. 1,3-Disubstituted ureas with a polar group located on the fifth atom from the carbonyl group of urea function are active inhibitors of sEH both in vitro and in vivo. However, their limited solubility in water and relatively high melting point lead to difficulties in formulating the compounds and poor in vivo efficacy. To improve these physical properties, the effect of structural modification of the urea pharmacophore on the inhibition potencies, water solubilities, octanol/water partition coefficients (log P), and melting points of a series of compounds was evaluated. For murine sEH, no loss of inhibition potency was observed when the urea pharmacophore was modified to an amide function, while for human sEH 2.5-fold decreased inhibition was obtained in the amide compounds. In addition, a NH group on the right side of carbonyl group of the amide pharmacophore substituted with an adamantyl group (such as compound 14) and a methylene carbon present between the adamantyl and amide groups were essential to produce potent inhibition of sEH. The resulting amide inhibitors have 10-30-fold better solubility and lower melting point than the corresponding urea compounds. These findings will facilitate synthesis of sEH inhibitors that are easier to formulate and more bioavailable.
机译：可溶性环氧化物水解酶（sEH）在涉及血压和炎症调节的内源性化学介质的代谢中起重要作用。具有在尿素功能的羰基的第五个原子上的极性基团的1，3-二取代的尿素在体外和体内都是sEH的活性抑制剂。然而，它们在水中的有限溶解性和相对较高的熔点导致难以配制化合物并且体内功效差。为了改善这些物理性质，评估了尿素药效团的结构修饰对一系列化合物的抑制能力，水溶性，辛醇/水分配系数（log P）和熔点的影响。对于鼠sEH，将尿素药效团修饰为酰胺功能时，没有观察到抑制力的损失，而对于人sEH，酰胺化合物中的抑制作用降低了2.5倍。另外，被金刚烷基（例如化合物14）取代的酰胺药效基团的羰基右侧的NH基团和金刚烷基与酰胺基之间存在的亚甲基碳对于有效抑制sEH是必不可少的。与相应的脲化合物相比，所得的酰胺抑制剂的溶解度高10-30倍，熔点更低。这些发现将促进易于配制和生物利用度的sEH抑制剂的合成。

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