Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA4 Hydrolase

Kerstin Hiesinger; Annika Schott; Jan S Kramer; René Blöcher; Finja Witt; Sandra K Wittmann; Dieter Steinhilber; Denys Pogoryelov; Jana Gerstmeier; Oliver Werz; Ewgenij Proschak

doi:10.1021/acsmedchemlett.9b00330

Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA₄ Hydrolase

ACS Med Chem Lett. 2019 Oct 30;11(3):298-302. doi: 10.1021/acsmedchemlett.9b00330. eCollection 2020 Mar 12.

Affiliations

¹ Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
² Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany.

Abstract

Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA₄ hydrolase (LTA₄H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-activity relationship studies were performed to identify optimal substitution patterns. X-ray structure analysis of a promising dual inhibitor in complex with sEH, as well as molecular docking with LTA₄H provided a rationale for further optimization. Hereby, scaffold extension was successfully applied to yield potent dual sEH/LTA₄H inhibitors. The spectrum of pro- and anti-inflammatory lipid mediators was evaluated in M1 and M2 macrophages, stimulated with LPS, and incubated with the most promising compound 14. The effect of 14 on the inflammatory lipid mediator profile characterizes dual sEH/LTA₄H inhibitors as an interesting option for future anti-inflammatory agent investigations.