Design of Dual Inhibitors of Soluble Epoxide Hydrolase and LTA₄ Hydrolase.

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 macrop

SUBMITTER: Hiesinger K 

PROVIDER: S-EPMC7073873 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature