Wang_2025_Future.Med.Chem__1

The development of soluble epoxide hydrolase (sEH) inhibitors has emerged as a promising therapeutic strategy, yet progress has been constrained by structural similarity and suboptimal pharmacokinetic profiles. While numerous synthetic and natural product-derived inhibitors demonstrate potent pharmacological activity, their clinical translation has been hampered by recurring limitations including poor solubility, low AUC, CYP inhibition, and hERG toxicity. This review critically evaluates recent breakthroughs in scaffold diversification and rational design approaches that overcome these limitations. We highlight innovative synthetic methodologies, structure-activity relationship insights, and novel chemotypes that expand the chemical space beyond conventional urea-based scaffolds. Furthermore, we discuss emerging therapeutic applications enabled by these advanced inhibitors, providing a strategic roadmap for next-generation sEH-targeted drug discovery.