Preparation and evaluation of soluble epoxide hydrolase inhibitors with improved physical properties and potencies for treating diabetic neuropathic pain.
Preparation and evaluation of soluble epoxide hydrolase inhibitors with improved physical properties and potencies for treating diabetic neuropathic pain.
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具有改善的物理性质和治疗糖尿病神经性疼痛的效力的可溶性环氧化物水解酶抑制剂的制备和评价。
DOI：
10.1016/j.bmc.2020.115735
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发表时间：
2020-11-15
影响因子：
3.5
通讯作者：
Hammock BD
中科院分区：
文献类型：
--
作者：
Lee KSS;Ng JC;Yang J;Hwang SH;Morisseau C;Wagner K;Hammock BD
可溶性环氧化物水解酶（Soluble epoxide hydrolase，sEH）是一种主要降解环氧脂肪酸（epoxy-fatty acids，EpFAs）的胞浆酶，是神经病理性疼痛的新治疗靶点。已经报道了许多sEH的抑制剂，并且迄今为止，在所评价的中心药效团中，1，3-二取代脲具有报道的对sEH的最高亲和力。早期用于临床血压控制的稍微水溶性的sEH抑制剂具有中等的效力（亲和力和动力学两者）和短的体内半衰期。我们进行了一项研究来克服这些困难，但携带1，3-二取代脲的sEH抑制剂通常具有较差的物理性质，这阻碍了它们的配制。在这份报告中，我们描述了用1，3-二取代脲改善sEH抑制剂的物理性质的新策略，同时保持其对sEH的效力和药物靶向停留时间（一个补充的体外参数）。令我们惊讶的是，我们确定了两个结构修饰，大大提高了携带1，3-二取代脲药效团的sEH抑制剂的效力和物理性质。此类改进将极大地促进sEH抑制剂进入临床。
Soluble epoxide hydrolase (sEH), a novel therapeutic target for neuropathic pain, is a largely cytosolic enzyme that degrades epoxy-fatty acids (EpFAs), an important class of lipid signaling molecules. Many inhibitors of sEH have been reported, and to date, the 1,3-disubstituted urea has the highest affinity reported for the sEH among the central pharmacophores evaluated. An earlier somewhat water soluble sEH inhibitor taken to the clinic for blood pressure control had mediocre potency (both affinity and kinetics) and a short in vivo half-life. We undertook a study to overcome these difficulties, but the sEH inhibitors carrying a 1,3-disubstituted urea often suffer poor physical properties that hinder their formulation. In this report, we described new strategies to improve the physical properties of sEH inhibitors with a 1,3-disubstituted urea while maintaining their potency and drug-target residence time (a complementary in vitro parameter) against sEH. To our surprise, we identified two structural modifications that substantially improve the potency and physical properties of sEH inhibitors carrying a 1,3-disubstituted urea pharmacophore. Such improvements will greatly facilitate the movement of sEH inhibitors to the clinic.
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影响因子：
1.7
作者：
Guedes AG;Morisseau C;Sole A;Soares JH;Ulu A;Dong H;Hammock BD
通讯作者：
Hammock BD
影响因子：
--
作者：
Huang SX;Cao B;Morisseau C;Jin Y;Hammock BD;Long YQ
通讯作者：
Long YQ
影响因子：
3.4
作者：
Daina, Antoine;Zoete, Vincent
通讯作者：
Zoete, Vincent
优化的可溶性环氧化物水解酶抑制剂可改善体外目标停留时间和体内功效。
影响因子：
7.3
作者：
Lee KS;Liu JY;Wagner KM;Pakhomova S;Dong H;Morisseau C;Fu SH;Yang J;Wang P;Ulu A;Mate CA;Nguyen LV;Hwang SH;Edin ML;Mara AA;Wulff H;Newcomer ME;Zeldin DC;Hammock BD
通讯作者：
Hammock BD
影响因子：
2.9
作者：
Chen, Dawn;Whitcomb, Randall;Webb, Heather K.
通讯作者：
Webb, Heather K.