Design, Synthesis, and In‐Vitro Evaluation of Novel Butanoic Acid Derivatives as Potential Soluble Epoxide Hydrolase Inhibitors

Soluble epoxide hydrolase (sEH) enzyme has been proposed as a promising target for the treatment of several peripheral inflammatory‐related diseases. The most potent sEH inhibitors are urea or amide‐based which play active‐site transition state mimic and often suffer from poor solubility and low bioavailability. Therefore, the development of novel sEH inhibitors with improved pharmacokinetic specification is a great deal of attention. In this study, amide‐based sEH inhibitors bearing N′‐acetylacetohydrazide/oxadiazole moieties as the primary (P1) and carboxyl/amide as secondary pharmacophores (P2) were designed, synthesized, and biologically evaluated. All the structures were confirmed via recruiting spectral data. Docking results demonstrated that the primary pharmacophore (P1) fit properly in the corresponding binding site of the enzyme, possessing appropriate distances for effective hydrogen bonding to the crucial amino acids, including Asp335. In agreement with the findings of docking studies, a number of compounds were found to possess moderate to high in‐vitro sEH inhibitory activities, and two compounds were identified as the most potent inhibitors with IC50 values of 7.8 and 10.98 nM, respectively. Furthermore, ADME properties of the newly designed analogs were analyzed in silico and the results showed that these compounds have the proper potential for being developed as new sEH inhibitors. Novel amide derivatives as soluble epoxide hydrolase inhibitors were developed. The in‐vitro assay revealed that most of the compounds exhibited moderate to high sEH inhibitory activity. The docking studies were in accordance with biological assays that showed all compounds fit well into the hydrolase active site of sEH and interact with key amino acid residues in the enzyme catalytic site.