Design, Synthesis, and Structure-Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5-Lipoxygenase.
Hiesinger K,Kramer JS,Beyer S,Eckes T,Brunst S,Flauaus C,Wittmann SK,Weizel L,Kaiser A,Kretschmer SBM,George S,Angioni C,Heering J,Geisslinger G,Schubert-Zsilavecz M,Schmidtko A,Pogoryelov D,Pfeilschifter J,Hofmann B,Steinhilber D,Schwalm S,Proschak E
Inhibition of multiple enzymes of the arachidonic acid cascade leads to synergistic anti-inflammatory effects. Merging of 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) pharmacophores led to the discovery of a dual 5-LOX/sEH inhibitor, which was subsequently optimized in terms of potency toward both targets and metabolic stability. The optimized lead structure displayed cellular activity in human polymorphonuclear leukocytes, oral bioavailability, and target engagement in vivo and demonstrated profound anti-inflammatory and anti-fibrotic efficiency in a kidney injury model caused by unilateral ureteral obstruction in mice. These results pave the way for investigating the therapeutic potential of dual 5-LOX/sEH inhibitors in other inflammation- and fibrosis-related disease models.