Rational Design, Synthesis, And Biological Validation of Therapeutically Effective Novel Sulfonamide Urea Derivatives as Soluble Epoxide Hydrolase Inhibitors

Authors

• B Kundu
• A Basu
• C Wood
• KA Kim
• L Pommerolle
• ER Gibbs
• M Behee
• R Cinar
• MR Lyer

Abstract

The enzyme soluble epoxide hydrolase (sEH) plays a pivotal role in the metabolism process of bioactive lipid signaling molecules. The substrate-specific hydrolase activity of sEH transforms epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs) purported to have inflammatory effects. It has been demonstrated that sEH inhibition leads to elevated levels of EETs, subsequently manifesting anti-inflammatory, analgesic, antihypertensive, cardio-protective, and organ-protective effects. Pharmacological inhibition of sEH in animal models exhibited beneficial effects on the treatment of hypertension, inflammation, and related syndromes. Although existing sEH inhibitors are potent and specific, low solubility and relatively fast metabolism decrease their therapeutic efficiency, stating the requirement for novel sEH inhibitors. Our research features rational design and synthesis of a series of novel compounds having potent soluble epoxide hydrolase inhibitory activity with enhanced solubility. A set of inhibitors have been found to exhibit better druggable properties and nanomolar potency in recombinant assays. We experimentally found these compounds synergistically inhibit sEH & iNOS (inducible Nitric Oxide Synthase), accounting for higher therapeutic efficacy. The potent compounds were evaluated in a panel of in vitro ADME assays and in vivo pharmacokinetic studies. The gene expression data from lipopolysaccharide (LPS)-induced acute lung injury (ALI) studies in mice demonstrated that the lead compound is more efficacious compared to a known sEH inhibitor AUDA to attenuate the inflammation caused by LPS in mice.Multi-target approach for improving the efficacy of sEH inhibitors either as a pro-drug, metabolite or whole drug will be presented.

Scientific Focus Area: Chemical Biology

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