Fragment-Based Discovery of Fenamic Acids as Pan-Species Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain.

Targeting the N-terminal phosphatase domain of soluble epoxide hydrolase (sEH) could potentially represent a pharmacological strategy for treatment of cardiometabolic diseases. However, development of chemical tools to investigate the therapeutic potential of sEH phosphatase (sEH-P) inhibition has proven challenging due to varying activities between different species isoforms and lack of selectivity toward the C-terminal hydrolase domain, which exhibits the epoxide hydrolase activity (sEH-H). Herein, we describe the fragment-based discovery of FZ581 (49), an sEH-P inhibitor against human, rat, and mouse isoforms. In vivo studies with this compound in mice and rats demonstrated a significant increase of main sEH-P substrate levels without affecting plasma levels of sEH-H substrates. Altogether, we provide a pan-species sEH-P inhibitor to study the pharmacotherapeutic potential of sEH-P inhibition.