Open AccessExploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation
Author(s) -
Konstantin Neukirch,
Khaled Alsabil,
Chau-Phi Dinh,
Rossella Bilancia,
Martin Raasch,
Alexia Ville,
Ida Cerqua,
Guillaume Viault,
Dimitri Bréard,
Simona Pace,
Veronika Temml,
Elena Brunner,
Paul M. Jordan,
Marta C. Marques,
Konstantin Loeser,
André Gollowitzer,
Stephan Permann,
Jana Gerstmeier,
Stefan Lorkowski,
Hermann Stuppner,
Ulrike Garscha,
Tiago Rodrigues,
Gonçalo J. L. Bernardes,
Daniela Schuster,
Denis Séraphin,
Pascal Richomme,
Antonietta Rossi,
Alexander S. Mosig,
Fiorentina Roviezzo,
Oliver Werz,
Jean-Jacques Hélesbeux,
Andreas Koeberle
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00806
Subject(s) - chemistry , inflammation , lipid signaling , pharmacology , immune system , endogeny , biochemistry , arachidonate 5 lipoxygenase , enzyme , leukotriene , eicosanoid , microsome , sulfation , arachidonic acid , immunology , biology , asthma
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 E 2 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.