Kodani Sean D, Hammock Bruce D
Department of Entomology and Nematology, Comprehensive Cancer Center, University of California, Davis, California.
Department of Entomology and Nematology, Comprehensive Cancer Center, University of California, Davis, California
Drug Metab Dispos. 2015 May;43(5):788-802. doi: 10.1124/dmd.115.063339. Epub 2015 Mar 11.
Dr. Bernard Brodie's legacy is built on fundamental discoveries in pharmacology and drug metabolism that were then translated to the clinic to improve patient care. Similarly, the development of a novel class of therapeutics termed the soluble epoxide hydrolase (sEH) inhibitors was originally spurred by fundamental research exploring the biochemistry and physiology of the sEH. Here, we present an overview of the history and current state of research on epoxide hydrolases, specifically focusing on sEHs. In doing so, we start with the translational project studying the metabolism of the insect juvenile hormone mimic R-20458 [(E)-6,7-epoxy-1-(4-ethylphenoxy)-3,7-dimethyl-2-octene], which led to the identification of the mammalian sEH. Further investigation of this enzyme and its substrates, including the epoxyeicosatrienoic acids, led to insight into mechanisms of inflammation, chronic and neuropathic pain, angiogenesis, and other physiologic processes. This basic knowledge in turn led to the development of potent inhibitors of the sEH that are promising therapeutics for pain, hypertension, chronic obstructive pulmonary disorder, arthritis, and other disorders.
伯纳德·布罗迪博士的遗产建立在药理学和药物代谢的基础发现之上，这些发现随后被应用于临床以改善患者护理。同样，一类名为可溶性环氧化物水解酶（sEH）抑制剂的新型治疗药物的开发最初是由探索sEH生物化学和生理学的基础研究推动的。在此，我们概述环氧化物水解酶的研究历史和现状，特别关注sEH。为此，我们从研究昆虫保幼激素类似物R-20458[（E）-6,7-环氧-1-（4-乙基苯氧基）-3,7-二甲基-2-辛烯]代谢的转化项目开始，该项目导致了哺乳动物sEH的鉴定。对这种酶及其底物（包括环氧二十碳三烯酸）的进一步研究，使人们深入了解了炎症、慢性和神经性疼痛、血管生成及其他生理过程的机制。这些基础知识进而促成了sEH强效抑制剂的开发，这些抑制剂有望用于治疗疼痛、高血压、慢性阻塞性肺疾病、关节炎及其他疾病。
