Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5‑LOX Inhibitor that Limits Inflammation

Endogenous long-chain
metabolites of vitamin E (LCMs) mediate immune
functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic
concentrations of resolvin E3, a specialized proresolving lipid mediator.
SAR studies on semisynthesized analogues highlight α-amplexichromanol
(27a), which allosterically inhibits 5-LOX, being considerably
more potent than endogenous LCMs in human primary immune cells and
blood. Other enzymes within lipid mediator biosynthesis were not substantially
inhibited, except for microsomal prostaglandin E2 synthase-1.
Compound 27a is metabolized by sulfation and β-oxidation
in human liver-on-chips and exhibits superior metabolic stability
in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung.
In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory
reaction is suppressed in reconstructed human epidermis, murine peritonitis,
and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation
with superior potency and metabolic stability to the endogenous lead.