Capan_2022_ChemMedChem__

Soluble epoxide hydrolase (sEH) is implicated as a potential therapeutic target for inflammation-related pathologies in the context of cardiovascular, central nervous system and metabolic diseases. In our search for novel sEH inhibitors, we designed and synthesized novel analogs of the piperazine urea derivative 4, a previously discovered dual microsomal prostaglandin E2 synthase-1 (mPGES-1)/soluble epoxide hydrolase (sEH) inhibitor, to evaluate their potential as sEH inhibitors. We identified two 1,3,4-oxadiazol-5-on and -thion congeners (compounds 19 and 20), which demonstrated selective sEH inhibition with IC50 values in the two-digit nanomolar range (42 and 56 nM, respectively). These results suggest that the installation of terminal 1,3,4-oxadiazol-5-on/thion functions to the benzyl end can be regarded as a promising secondary pharmacophore in addition to the urea group for sEH inhibition, and compound 19 can be regarded as novel lead structure for further optimization of improved sEH inhibitors.