Burmistrov Vladimir, Morisseau Christophe, Pitushkin Dmitry, Fayzullin Robert R, Karlov Dmitry, Vernigora Andrey, Kuznetsov Yaroslav, Abbas Saeef M H, Butov Gennady M, Hammock Bruce D
Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA.
Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (branch) Volgograd State Technical University, Volzhsky, 404121, Russia.
Results Chem. 2022 Jan;4. doi: 10.1016/j.rechem.2022.100653. Epub 2022 Nov 16.
The soluble epoxide hydrolase (sEH) is a potential target to treat cardiovascular, renal and neuronal diseases. A series of sEH inhibitors containing naturally occurring lipophilic groups (originating from camphor and fenchone) were developed. Inhibitory potency ranging from 0.7 nM to 6.47 μM was obtained. It was discovered that ureas derived from L-camphor were more active against sEH (2.3-fold average) than the corresponding analogues derived from D-camphor indicating enantiomeric preference of sEH. Ureas derived from fenchone possess lower activity against sEH (ca. 80-fold on average) than their camphor-derived analogs due to the specific structure of the lipophilic fragment and show less enantiomeric preference (1.75-fold on average). Moreover, fenchone-derived ureas show no consistency in enantiomeric preference. /-form of compound derived from L-camphor is 4-fold more potent than the corresponding analogue prepared from D-camphor (IC = 0.7 nM vs. 2.8 nM) making it the most promising sEH inhibitor among the tested series.
可溶性环氧化物水解酶（sEH）是治疗心血管、肾脏和神经疾病的潜在靶点。人们开发了一系列含有天然亲脂性基团（源自樟脑和葑酮）的sEH抑制剂。其抑制效力范围为0.7 nM至6.47 μM。研究发现，源自L-樟脑的脲对sEH的活性比源自D-樟脑的相应类似物更高（平均高2.3倍），这表明sEH存在对映体偏好。由于亲脂性片段的特定结构，源自葑酮的脲对sEH的活性比其源自樟脑的类似物低（平均约80倍），且对映体偏好性较小（平均1.75倍）。此外，源自葑酮的脲在对映体偏好方面没有一致性。源自L-樟脑的化合物的/-形式比由D-樟脑制备的相应类似物效力高4倍（IC = 0.7 nM对2.8 nM），使其成为测试系列中最有前景的sEH抑制剂。
