14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) Surrogates Containing Epoxide Bioisosteres: Influence upon Vascular Relaxation and Soluble Epoxide Hydrolase Inhibition

Abstract

All-cis-14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a labile, vasodilatory eicosanoid generated from arachidonic acid by cytochrome P450 epoxygenases. A series of robust, partially saturated analogs containing epoxide bioisosteres were synthesized and evaluated for relaxation of precontracted bovine coronary artery rings and for in vitro inhibition of soluble epoxide hydrolase (sEH). Depending upon the bioisostere and its position along the carbon chain, varying levels of vascular relaxation and/or sEH inhibition were observed. For example, oxamide 16 and N-iPr-amide 20 were comparable (ED50 1.7 μM) to 14,15-EET as vasorelaxants, but were approx. 10–35 times less potent as sEH inhibitors (IC50 59 and 19 μM, respectively); unsubstituted urea 12 showed useful activity in both assays (ED50 3.5 μM, IC50 16 nM). These data reveal differential structural parameters for the two pharmacophores that could assist the development of potent and specific in vivo drug candidates.

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

“…They include the potent N,N ′ - disubstituted urea inhibitors like AUDA, and those with higher water solubility such as trans- 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid ( t- AUCB), and 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)urea (TUPS) [60]. Dual function sEH inhibitors are available now, including those that also serve as stable EET analogues such as 8-HUDE (12-(3-hexylureido) dodec-8-enoic acid) [61,62], those that modulate peroxisome proliferator-activated receptors [63], and those that inhibit 5-lipoxygenase [64]. In addition, inhibitors with new pharmacophores are being developed [65–67], including urea-containing-pyrazoles that are dual inhibitors of sEH and cyclooxygenase-2 [68].…”

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…For example, given the antiinflammatory and antihypertensive actions of 11,12-EET and 14,15-EET, structural stable (sEH insensitive) EET analogs may be the best way to proceed. Compounds that mimic as well as antagonize the actions of the EETs have been developed (Gauthier et al, 2004; Vascular P450/sEH Axis Falck et al, 2009) and show effectiveness in different models (Bukhari et al, 2012;Hye Khan et al, 2013Khan et al, 2013). Another approach would be to target specific PUFA epoxide receptors, such as the EET receptor; however, this approach can only begin once the putative EET receptors have been identified.…”

Midkine Regulates BP through Cytochrome P450–Derived Eicosanoids

“…Because EETs are involved in dilation of small arteries, 7,11,37,38 it is supposed that EETs may play a role in the axis of endothelial dysfunction and reduced vasodilation. As shown Figure 6, an EET antagonist significantly suppressed peritubular capillary blood flow in Mdk 2/2 mice, but not in wild-type mice.…”

“…44 EETs can reduce BP by a combination of a reduction in renal tubular sodium reabsorption [45][46][47] and dilation of blood vessels. 7,11,37,38 EETs also inhibit inflammation and platelet aggregation. [39][40][41] Thus, MK-targeted therapy may treat not only hypertension, but also other diseases complicated by endothelial dysfunction, such as cardiovascular diseases, cerebrovascular diseases, CKD, and diabetes.…”