Abstract
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.
Footnotes
- Received January 15, 2015.
- Accepted March 11, 2015.
This research was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grants R01-ES002170 and P42-ES004699], the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant R21-AR062866], and the Research Investments in the Science and Engineering Program at the University of California, Davis. B.D.H. is a cofounder of EicOsis LLC, and he has several patents on soluble epoxide hydrolase technology.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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