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

J Med Chem. 2021 Aug 12;64(15):11496-11526. doi: 10.1021/acs.jmedchem.1c00806. Epub 2021 Jul 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Arachidonate 5-Lipoxygenase / genetics
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • 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*

Substances

  • Lipoxygenase Inhibitors
  • Recombinant Proteins
  • Vitamin E
  • Arachidonate 5-Lipoxygenase