Synthesis and Structure–Activity Relationship Studies of Novel Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase

Abstract

Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors. Evaluation of the compounds was accomplished by in vitro testing using recombinant enzyme assays.

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

“…Such shunting responses could also account for the report that the long-term inhibition of the sEH increases plasma levels of LOX products, a phenomenon linked with more severe albuminuria in a murine model of kidney disease (Jung et al, 2010). Because COX and LOX products tend to be proinflammatory, the answer may be to use a combined target approach (i.e., sEH inhibition combined with COX or LOX inhibition) (Hwang et al, 2011;Meirer et al, 2013). Certainly, the coadministration of an sEH inhibitor and aspirin or the 5-LOX activation protein inhibitor MK886 (1-[(4-chlorophenyl)methyl]-3-[(1, 1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid) enhanced the antiinflammatory effect and resulted in better control of lipopolysaccharide-induced hypotension as well as hepatic protein expression of COX2 and 5-LOX (Liu et al, 2010a;Hwang et al, 2011).…”

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 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

“…Along with increased potency, the PK has shifted from highly aliphatic and quickly metabolized inhibitors to compounds with long half-lives in a variety of species, including dogs and nonhuman primates Ulu et al, 2012). Inhibitors have also evolved for multitarget engagement toward cyclooxygenase (COX) (Hwang et al, 2011) and lipoxygenase (Meirer et al, 2013). Dual sEH/COX inhibition results in synergism that dramatically improves the potency of compounds (Zhang et al, 2014b).…”