Topliss‐Guided Optimization of Acetanilide‐Based Soluble Epoxide Hydrolase Inhibitors: Exploring the Pentafluorosulfanyl Group as a Potency‐Enhancing Motif

The inhibition of soluble epoxide hydrolase (sEH) has emerged as an attractive therapeutic strategy through the stabilization of endogenous bioactive epoxyeicosatrienoic acids. Most of the inhibitors developed to date contain a central urea pharmacophore; however, these compounds often suffer from physicochemical limitations, particularly limited aqueous solubility. Herein, we report the design, synthesis, and biological evaluation of a new family of 2-(1-benzylpiperidin-4-yl)acetamides inspired by the reference sEH inhibitor 1-(1-propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (TPPU). Replacement of the urea pharmacophore in TPPU with an amide significantly improved aqueous solubility but reduced inhibitory potency. Surprisingly, substitution of the trifluoromethyl group of TPPU with a pentafluorosulfanyl substituent restored potency against human sEH, leading to the identification of a promising hit compound. Subsequent structure-activity relationship studies guided by the Topliss Batchwise Scheme (TBS) enabled systematic optimization of the aromatic substitution pattern and revealed that electronic effects are the main drivers of inhibitory potency, leading to several analogs displaying strong activity across human, mouse, and rat sEH. However, their further development was discontinued due to safety-related liabilities identified during the screening cascade. Nevertheless, these results highlight the utility of the underexplored pentafluorosulfanyl group and the TBS strategy for optimizing amide-based sEH inhibitors.