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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.

Published version
Peer-reviewed

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Authors

Neukirch, Konstantin  ORCID logo  https://orcid.org/0000-0003-0630-1624
Alsabil, Khaled 
Dinh, Chau-Phi 
Bilancia, Rossella 
Raasch, Martin 

Abstract

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.

Description

Keywords

Administration, Oral, Arachidonate 5-Lipoxygenase, Dose-Response Relationship, Drug, Drug Discovery, Humans, Inflammation, Lipoxygenase Inhibitors, Molecular Docking Simulation, Molecular Structure, Recombinant Proteins, Structure-Activity Relationship, Vitamin E

Journal Title

J Med Chem

Conference Name

Journal ISSN

0022-2623
1520-4804

Volume Title

64

Publisher

American Chemical Society (ACS)