Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase

Abstract

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P₂ ) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P₁ ) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC₅₀ value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.

Keywords: docking; inhibitor; phthalimide; soluble epoxide hydrolase; synthesis.