Pecic Stevan, Zeki Amir A, Xu Xiaoming, Jin Gina Y, Zhang Shuwei, Kodani Sean, Halim Marlin, Morisseau Christophe, Hammock Bruce D, Deng Shi-Xian
Department of Medicine, Columbia University, 650 W 168th Street, BB1029, New York, NY 10032, USA.
University of California, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis, CA 95616, USA.
Prostaglandins Other Lipid Mediat. 2018 May;136:90-95. doi: 10.1016/j.prostaglandins.2018.02.004. Epub 2018 Mar 20.
We have previously identified and reported several potent piperidine-derived amide inhibitors of the human soluble epoxide hydrolase (sEH) enzyme. The inhibition of this enzyme leads to elevated levels of epoxyeicosatrienoic acids (EETs), which are known to possess anti-inflammatory, vasodilatory, and anti-fibrotic effects. Herein, we report the synthesis of 9 analogs of the lead sEH inhibitor and the follow-up structure-activity relationship and liver microsome stability studies. Our findings show that isosteric modifications that lead to significant alterations in the steric and electronic properties at a specific position in the molecule can reduce the efficacy by up to 75-fold. On the other hand, substituting hydrogen with deuterium produces a notable increase (∼30%) in the molecules' half-lives in both rat and human microsomes, while maintaining sEH inhibition potency. These data highlight the utility of isosteric replacement for improving bioavailability, and the newly-synthesized inhibitor structures may thus, serve as a starting point for preclinical development. Our docking study reveals that in the catalytic pocket of sEH, these analogs are in proximity of the key amino acids involved in hydrolysis of EETs.
我们之前已鉴定并报道了几种有效的源自哌啶的人可溶性环氧化物水解酶（sEH）酰胺抑制剂。抑制这种酶会导致环氧二十碳三烯酸（EETs）水平升高，已知EETs具有抗炎、血管舒张和抗纤维化作用。在此，我们报告先导sEH抑制剂的9种类似物的合成以及后续的构效关系和肝微粒体稳定性研究。我们的研究结果表明，导致分子特定位置的空间和电子性质发生显著改变的等排体修饰可使功效降低多达75倍。另一方面，用氘取代氢会使分子在大鼠和人微粒体中的半衰期显著增加（约30%），同时保持sEH抑制效力。这些数据突出了等排体替代在提高生物利用度方面的效用，因此新合成的抑制剂结构可能作为临床前开发的起点。我们的对接研究表明，在sEH的催化口袋中，这些类似物靠近参与EETs水解的关键氨基酸。
