14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) Surrogates: Carboxylate Modifications

Abstract

The cytochrome P450 eicosanoid 14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a powerful endogenous autacoid that has been ascribed an impressive array of physiologic functions including regulation of blood pressure. Because 14,15-EET is chemically and metabolically labile, structurally related surrogates containing epoxide bioisosteres were introduced and have become useful in vitro pharmacologic tools but are not suitable for in vivo applications. A new generation of EET mimics incorporating modifications to the carboxylate were prepared and evaluated for vasorelaxation and inhibition of soluble epoxide hydrolase (sEH). Tetrazole 19 (ED50 0.18 μM) and oxadiazole-5-thione 25 (ED50 0.36 μM) were 12- and 6-fold more potent, respectively, than 14,15-EET as vasorelaxants; on the other hand, their ability to block sEH differed substantially, i.e., 11 vs >500 nM. These data will expedite the development of potent and specific in vivo drug candidates.

Epoxyeicosatrienoic Acids, Hypertension, and Kidney Injury

“…61 The next generation of EET analogs removed the 1,4-diene responsible for autoxidation and replaced the labile epoxide with bio-isosteres that resist metabolism (Figure 2). 61,62 Studies of the second generation of EET analogs assessing vascular inflammation and dilation resulted in the following structural requirements: an acidic carboxyl group, Δ 8 olefin bond, 20-carbon chain length, and a cis epoxide. 61,62 …”

Orally Active Epoxyeicosatrienoic Acid Analogs

“…Importantly, increasing the steric size of the nitrogen substituent from N -methyl 21 to N -isopropyl 22 significantly boosted the vasorelaxation efficacy. On the other hand, reversing the placement order of the amide, 20 vs 23 , almost abolished the analogs ability to relax the vessels (121). Oxamide 24 stands out as a good choice for a reagent that displays EET-like EDHF effects, yet has little sEH inhibitory activity.…”

“…Collectively, they comprise the third generation of 14,15-EET analogs and were mainly targeted at minimizing or preventing β-oxidation and esterification while simultaneously promoting better water solubility, improving oral bioavailability, and extending in vivo half-life (121). Some typical examples are shown in Table 2.…”

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

“…Extensive experimental evaluation of the CYP and LO genes and proteins has led to excellent definition of the catalytic site for the enzymes resulting in the design and development of selective pharmacological inhibitors (4, 33, 50, 56, 119, 127). These pharmacological tools have been instrumental for evaluating the biological actions of CYP and LO enzymes in renal cell culture systems, isolated renal vascular, and tubular preparations, and in vivo .…”

“…These EET analogs have been designed to have increase solubility and resist sEH and β-oxidative metabolism (16, 33, 53, 127). First generation EET analogs were methyl esters and sulfonamide substitutions of the carboxylic acid which obviated esterification and resisted β-oxidation (57).…”