Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.
Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.
复制标题
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。
DOI：
10.1021/jm500694p
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发表时间：
2014-08-28
影响因子：
7.3
通讯作者：
Hammock BD
中科院分区：
文献类型：
--
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
糖尿病影响着数百万人的生活。大部分糖尿病患者患有严重的并发症，如神经性疼痛，目前对这些并发症的治疗具有有害的副作用。因此，需要替代治疗策略。最近，通过抑制可溶性环氧化物水解酶（sEH）提高环氧脂肪酸显示出减少啮齿动物的糖尿病神经性疼痛。在这份报告中，我们描述了一系列新合成的sEH抑制剂，与以前报道的抑制剂相比，其在人和啮齿动物sEH酶内的效力至少高5倍，停留时间加倍。这些抑制剂还具有更好的物理性质和优化的药代动力学特征。与批准的药物加巴喷丁和先前发表的sEH抑制剂相比，从该新系列中选择的优化抑制剂在缓解糖尿病神经病大鼠的疼痛感知方面显示出几乎10倍的改善功效。因此，这些新的sEH抑制剂可能是治疗人类糖尿病神经病变的有吸引力的替代方案。
Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
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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：
7.3
作者：
Hwang, Sung Hee;Tsai, Hsing-Ju;Hammock, Bruce D.
通讯作者：
Hammock, Bruce D.
DOI：
10.1038/nrd2875
发表时间：
2009-10
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1107/s0907444994003112
发表时间：
1994-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
BAILEY, S
通讯作者：
BAILEY, S