ACS chemical biology · 2026
Fragment-Based Discovery of Fenamic Acids as Pan-Species Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain.
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Zhu W Felix, Feugray Guillaume, Brunst Steffen, Messaoudi Hind, Yang Meng, Martinez-Conde Noemi, Krämer Andreas, Weizel Lilia, Ehrler Johanna M H, Kramer Jan S, Kaiser Astrid, Al-Tarrass Mohammad, Pereira Tony, Valet Manon, Brunel Valéry, Schubert-Zsilavecz Manfred, Knapp Stefan, Lillich Felix F, Hernandez-Olmos Victor, Duflot Thomas, Hiesinger Kerstin, Qian Hongwu, Proschak Anna, Bellien Jeremy, Proschak Ewgenij
Аннотация
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.