Eicosanoids are metabolites derived from arachidonic acid (AA), generated through three enzymatic routes, namely cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) pathways. These lipid mediators play a crucial role in regulating inflammation and pain [1]. While the COX and LOX pathways have been extensively studied for drug discovery efforts for several decades [[2], [3], [4]], the CYP450 pathway remains an emerging field with significant potential for developing effective treatments for inflammation-related diseases, pain, and cancer [1,5,6]. The CYP450 pathway converts AA into a range of products, including monohydroxy fatty acids (e.g., hydroxyeicosatetraenoic acids or HETEs) and epoxy fatty acids (EpFAs) such as epoxy-eicosatrienoic acids (EETs) (Fig. 1). EpFAs, particularly EETs, act mainly as autocrine and paracrine signaling molecules, exerting beneficial effects under various conditions related to cardiovascular diseases, renal function, angiogenesis, pain, inflammation, and cancer [[7], [8], [9]]. EETs are predominantly converted into dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). This conversion impairs the beneficial effects of EETs, as DHETs possess different functions under normal conditions. Thus, inhibiting sEH helps to maintain EET levels, prolonging their bioactivity, and maximizing their potential as therapeutic agents. In this respect, inhibitors of sEH have emerged as a promising strategy for managing pain, cancer, and inflammatory conditions [[10], [11], [12], [13], [14]].

The most effective sEH inhibitors identified so far have been 1,3-disubstituted urea and amide derivatives, recognized for their antihypertensive, analgesic, anti-inflammatory, and anti-cancer effects [[10], [11], [12],[15], [16], [17], [18], [19]], with several of these compounds advancing to clinical development (Fig. 2). These inhibitors typically feature extensive hydrophobic and/or aromatic regions surrounding the central urea or amide core, which forms hydrogen bonds with key active site residues—Tyr381, Tyr465, and Asp333—of the sEH enzyme [20]. However, most of these inhibitors frequently exhibit poor solubility and bioavailability, limiting their effectiveness in vivo. Accordingly, our design strategy focused on concurrently enhancing both biological activity and key physicochemical properties. To this end, we recently proposed a novel structural approach that introduces a secondary pharmacophore—specifically, a heteroaryl functional group with hydrogen bond donor/acceptor capabilities—alongside the primary urea pharmacophore with the aim to improve binding affinity and modulate physicochemical properties (Fig. 2) [[21], [22], [23]]. The addition of these secondary pharmacophores enabled the compounds to form direct or water-mediated hydrogen bonds with polar amino acids such as Gln384 and Asn472 in the long branch of the sEH active site, interactions that have been previously documented in specific inhibitor clusters [24].

During the past decade, our research has centered on developing novel anti-inflammatory agents targeting multiple biological pathways within the AA cascade, including sEH [[21], [22], [23],[25], [26], [27], [28], [29]]. In this context, we performed an in-depth analysis of sEH crystallographic and fragment screening data alongside a thorough review of existing SAR information for sEH inhibitors, to propose novel inhibitor chemotypes [24,[30], [31], [32]]. Thus, we here report the successful discovery of novel thiazole-5-carboxamide derivatives featuring a 2-oxo-imidazolidine group as a secondary pharmacophore, effectively inhibiting sEH. These compounds demonstrate high metabolic stability and excellent solubility, positioning them as promising candidates for further development as potential anti-inflammatory and analgesic agents.