Design, Synthesis, and Structure–Activity Relationship Studies of Dual Inhibitors of Soluble Epoxide Hydrolase and 5‑Lipoxygenase

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.