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.
Neukirch K, Alsabil K, Dinh CP, Bilancia R, Raasch M, Ville A, Cerqua I, Viault G, Bréard D, Pace S, Temml V, Brunner E, Jordan PM, Marques MC, Loeser K, Gollowitzer A, Permann S, Gerstmeier J, Lorkowski S, Stuppner H, Garscha U, Rodrigues T, Bernardes GJL, Schuster D, Séraphin D, Richomme P, Rossi A, Mosig AS, Roviezzo F, Werz O, Helesbeux JJ, Koeberle A.
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 (<b>27a</b>), 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 E<sub>2</sub> synthase-1. Compound <b>27a</b> 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 <b>27a</b> 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 <b>27a</b> as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.