Harnessing structure-activity relationships to repurpose the FLAP inhibitor BRP-7 into potent and selective sEH inhibitors

Soluble epoxide hydrolase (sEH) has emerged as a validated therapeutic target in inflammation-related conditions, particularly in cardiovascular, metabolic, and central nervous system disorders. In this study, we report the rational design, synthesis, and biological evaluation of a new class of benzimidazole-based amide derivatives as potent and selective inhibitors of sEH. These compounds were developed by scaffold optimization of BRP-7, a previously reported FLAP inhibitor, through strategic modifications at the C(2) and C(5) positions of the benzimidazole core, guided by SAR insights. Among the synthesized analogs, FP30 (BRP-821) exhibited exceptional sub-nM sEH inhibitory activity (IC₅₀ = 0.4 nM), along with excellent metabolic stability in human liver microsomes (t_1/2 > 184 min, ER < 0.27) and high solubility in simulated intestinal fluid (108 μM). Notably, the lead compounds demonstrated high selectivity over FLAP, distinguishing this new chemotype from dual inhibitors. Collectively, these findings highlight a promising new scaffold for further optimization toward the development of sEH-targeted therapeutics for the treatment of neuropathic pain and inflammatory diseases.