Development of multitarget agents possessing soluble epoxide hydrolase inhibitory activity

Abstract

Over the last two decades polypharmacology has emerged as a new paradigm in drug discovery, even though developing drugs with high potency and selectivity toward a single biological target is still a major strategy. Often, targeting only a single enzyme or receptor shows lack of efficacy. High levels of inhibitor of a single target also can lead to adverse side effects. A second target may offer additive or synergistic effects to affecting the first target thereby reducing on-and off-target side effects. Therefore, drugs that inhibit multiple targets may offer a great potential for increased efficacy and reduced the adverse effects. In this review we summarize recent findings of rationally designed multitarget compounds that are aimed to improve efficacy and safety profiles compared to those that target a single enzyme or receptor. We focus on dual inhibitors/modulators that target the soluble epoxide hydrolase (sEH) as a common part of their design to take advantage of the beneficial effects of sEH inhibition.

Epoxy-Oxylipins and Soluble Epoxide Hydrolase Metabolic Pathway as Targets for NSAID-Induced Gastroenteropathy and Inflammation-Associated Carcinogenesis

“…Downstream active molecules from ARA metabolism include prostaglandins (PGs), leukotrienes, epoxyeicosanoids, and hydroxyeicosatetraenoic acid. In addition to ARA, other polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are also substrates for these same enzymes (Hiesinger et al, 2019). Of particular interest are the epoxyeicosatrienoic acids (EETs), the metabolites of cytochrome p450 epoxygenase.…”

“…These diol-containing DHETs have drastically reduced biologic activity. Thus, inhibition of sEH has been extensively studied as a mechanism to increase the longevity of anti-inflammatory EETs via the discovery of sEH inhibitors, particularly in combination with other inhibitors as multi-target therapies, which were recently reviewed (Hiesinger et al, 2019). sEH inhibitors have been shown to robustly decrease sEH activity with little to no toxicity in animal models.…”

Novel Sulfonamide-Based Analogs of Metformin Exert Promising Anti-Coagulant Effects without Compromising Glucose-Lowering Activity

“…The multi-target strategy has become one of today’s most promising drug discovery areas, particularly in developing medicines against complex diseases [ 25 ]. The review of FDA-approved new drugs from 2000 to 2015 [ 26 ] supports the idea that poly-pharmacology is particularly useful for treating diseases with complex etiology, including inflammation, cancer and metabolic syndrome [ 27 ]. It has been accepted that simultaneous influence of multiple targets is required to manage diseases with complex pathology.…”

New Lipid Mediators in Retinal Angiogenesis and Retinopathy

“…The biological activity of the PUFA epoxides is regulated by their hydrolysis to diols by the epoxide hydrolases that, for example, generate dihydroxyeicosatrienoic acids (DHETs) from the EETs ( Figure 1 ); although 5,6–EET seems to be a preferred substrate for cyclooxygenase enzymes. The best studied epoxide hydrolase is the soluble epoxide hydrolase (sEH; gene name Ephx2 ); reviewed in Morisseau and Hammock (2005)and Hiesinger et al (2019), but there are three other members of the protein family that include the microsomal epoxide hydrolase (gene name Ephx1 ) as well as EPHX3 and EPHX4 (Decker et al, 2012). While the microsomal epoxide hydrolase has also been implicated in the regulation of epoxide diol levels in some situations (Edin et al, 2018) and EPHX4 has yet to be studied in detail, Ephx3 −/− mice do not demonstrate clear alterations in epoxide:diol ratios even though the enzyme was reported to catalyze the hydrolysis of 11,12-EET and the linoleic acid epoxide 9,10-epoxyoctadecamonoenoic acid (EpOME) in vitro (Hoopes et al, 2017).…”