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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-08, Vol.64 (15), p.11496-11526
Main Authors: Neukirch, Konstantin, Alsabil, Khaled, Dinh, Chau-Phi, Bilancia, Rossella, Raasch, Martin, Ville, Alexia, Cerqua, Ida, Viault, Guillaume, Bréard, Dimitri, Pace, Simona, Temml, Veronika, Brunner, Elena, Jordan, Paul M, Marques, Marta C, Loeser, Konstantin, Gollowitzer, André, Permann, Stephan, Gerstmeier, Jana, Lorkowski, Stefan, Stuppner, Hermann, Garscha, Ulrike, Rodrigues, Tiago, Bernardes, Gonçalo J. L, Schuster, Daniela, Séraphin, Denis, Richomme, Pascal, Rossi, Antonietta, Mosig, Alexander S, Roviezzo, Fiorentina, Werz, Oliver, Helesbeux, Jean-Jacques, Koeberle, Andreas
Format: Article
Language:English
Subjects:
Administration, Oral
Arachidonate 5-Lipoxygenase - genetics
Arachidonate 5-Lipoxygenase - metabolism
Chemical Sciences
Dose-Response Relationship, Drug
Drug Discovery
Humans
Inflammation - drug therapy
Inflammation - metabolism
Life Sciences
Lipoxygenase Inhibitors - administration & dosage
Lipoxygenase Inhibitors - metabolism
Lipoxygenase Inhibitors - pharmacology
Molecular Docking Simulation
Molecular Structure
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Structure-Activity Relationship
Vitamin E - administration & dosage
Vitamin E - metabolism
Vitamin E - pharmacology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00806