Discovery of Inhibitors of Soluble Epoxide Hydrolase: A Target with Multiple Potential Therapeutic Indications

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

“…To investigate the synergistic interactions of COX-2 and sEH on cancer further, we studied the role of the COX-2/sEH dual pharmacological inhibitors in angiogenesis and cancer. A dual inhibitor, PTUPB, inhibits sEH with IC 50 = 0.9 nM, which is comparable to the selective sEHIs developed in our laboratory (19). It is a COX-2-selective inhibitor with IC 50 = 1.26 μM for COX-2 and IC 50 > 100 μM for COX-1, and it is more potent than rofecoxib (Vioxx) and indomethacin (Indocin) for COX-2 inhibition (9).…”

“…Some selectivity in favor of sEH is desirable because complete inhibition of an enzyme degrading an apparently beneficial lipid mediator is attractive (5). Also, the sEHIs studied to date appear to have a massive therapeutic index compared with a more limited one with COX inhibitors (19). More potent COX inhibition may be desirable; however, this could be challenging because in vitro COX assays correlate weakly with in vivo efficacy (4) and PTUPB is already more potent than many marketed NSAIDs and coxibs for COX-2 inhibition (9).…”

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

“…Our fi ndings offer important insight into the potential therapeutic utility of increasing EETs in obstructive CAD patients predisposed to low EET levels. Importantly, agents that promote the effects of EETs are in early development for a variety of therapeutic indications (47)(48)(49). In parallel, technology for the high-throughput by guest, on May 7, 2018 www.jlr.org Downloaded from .html http://www.jlr.org/content/suppl/2015/11/10/jlr.M061697.DC1 Supplemental Material can be found at:…”

The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases

“…However, the results of animal studies cannot be applied in humans. A clinical trial of the sEHI 1-(1-acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea, designed for the treatment of hypertension and impaired glucose tolerance, was terminated in November 2009, because it did not appear to have any effect in phase II studies (67). Another sEHI, GSK2256294, has entered a phase I clinical trial for the treatment of chronic obstructive pulmonary disease (clinicaltrials.gov; ID: NCT01762774).…”