Lengerli_2025_Bioorg.Chem_163_108644

Epoxyeicosatrienoic acids (EETs) possess a range of beneficial biological effects, including anti-inflammatory and analgesic properties, but their bioactions are limited by rapid degradation through soluble epoxide hydrolase (sEH). Hence, inhibiting sEH to sustain elevated EET levels has become an attractive therapeutic strategy with significant clinical potential for treating various inflammatory conditions and pain. In this study, we integrated the favorable structural features identified in earlier structure-activity relationship (SAR) studies to design a novel class of thiazole-5-carboxamides, which are functionalized with a 2-oxo-imidazolidine group as the secondary pharmacophore and are flanked by benzyl groups at both ends. Our SAR studies demonstrated that ortho- and ortho/para-substituted benzyl groups at the carboxamide end, along with the 2-oxo-imidazolidine moiety, are the most effective structural features for achieving high potency, connected to favorable physical properties and metabolic stability. The benchmark compound 2-(3-(3-chlorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-methoxy-2-(trifluoromethyl)benzyl)thiazole-5-carboxamide (50) showed potent inhibition of the human sEH enzyme with an IC(50) of 0.46 nM and exhibited outstanding metabolic stability (t(1/2) = 126 min, ER = 0.35) in human liver microsomes, as well as excellent solubility in simulated intestinal fluid (116 microM).