Soluble Epoxide Hydrolase Inhibitors and their Potential for Treatment of Multiple Pathologic Conditions

R.      H. Ingraham; R.      D. Gless; H.      Y. Lo

Abstract

Epoxyeicosanoids, including the epoxyeicosatrienoic acids, are signaling molecules which appear to help ameliorate the effects of a wide variety of pathological conditions. The enzyme soluble epoxide hydrolase (sEH) metabolizes these molecules by converting them to their corresponding vicinal diols. Inhibition of sEH either by knockout or chemical inhibitors increases epoxyeicosanoid levels in vivo and provides significant organ protection in models of brain, cardiac, and renal injury. sEH also appears to be involved in modulating inflammation, pain pathways, pulmonary function, hypertension, and diabetes. Potent sEH inhibitors have been developed in academic, pharmaceutical, and biotech laboratories and described in the patent and scientific literature. Most of the inhibitor scaffolds employ a urea or amide which functions as an active-site transition state mimic. Arete Therapeutics compound AR9281 successfully completed phase Ia and Ib studies. A phase IIa proof of concept trial for treatment of impaired glucose tolerance has been completed, but the results are not yet reported.

Keywords: AR9281, BTP2, EPHX2, epoxyeicosatrienoic acid, eicosanoids, sEH, soluble epoxide hydrolase, Multiple Pathologic Conditions, Epoxyeicosanoids, ameliorate, vicinal diols, homodimeric bifunctional enzyme, linoleic acid, pyrophosphates, farnesyl, geranyl-geranyl, cytosol,, endothelial-derived hyperpolarizing factor, transient ischemic attack (TIA), MCAO (Middle Cerebral, HAMMOCK LABORATORY PHARMACOPHORE MODEL, secondary pharmacophore, am-ide, ketone, alcohol, carbamate, benzoheterocycle, alkyl spacers, adamantane piperidinyl ureas, piperidinyl ureas, BOEHRINGER INGELHEIM, HOFFMAN LA ROCHE, TAISHO, MERCK