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 - Substances d'Origine Naturelle et Analogues Structuraux Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2021

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

Konstantin Neukirch
Rossella Bilancia
  • Fonction : Auteur
Martin Raasch
  • Fonction : Auteur
Ida Cerqua
  • Fonction : Auteur
Simona Pace
  • Fonction : Auteur
Veronika Temml
  • Fonction : Auteur
Elena Brunner
  • Fonction : Auteur
Paul Jordan
  • Fonction : Auteur
Marta Marques
  • Fonction : Auteur
Konstantin Loeser
  • Fonction : Auteur
André Gollowitzer
  • Fonction : Auteur
Stephan Permann
  • Fonction : Auteur
Jana Gerstmeier
  • Fonction : Auteur
Stefan Lorkowski
  • Fonction : Auteur
Hermann Stuppner
Ulrike Garscha
  • Fonction : Auteur
Tiago Rodrigues
  • Fonction : Auteur
Gonçalo Bernardes
Daniela Schuster
Antonietta Rossi
  • Fonction : Auteur
Alexander Mosig
Fiorentina Roviezzo
  • Fonction : Auteur
Oliver Werz
Andreas Koeberle

Résumé

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 βoxidation 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.
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hal-03783673 , version 1 (22-09-2022)

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Konstantin Neukirch, Khaled Alsabil, Chau-Phi Dinh, Rossella Bilancia, Martin Raasch, et al.. 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. Journal of Medicinal Chemistry, 2021, 64 (15), pp.11496-11526. ⟨10.1021/acs.jmedchem.1c00806⟩. ⟨hal-03783673⟩
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