ZFIN ID: ZDB-PUB-190820-8
Second generation inhibitors of the mitochondrial permeability transition pore with improved plasma stability
Sileikyte, J., Devereaux, J., de Jong, J., Schiavone, M., Jones, K., Nilsen, A., Bernardi, P., Forte, M., Cohen, M.
Date: 2019
Source: ChemMedChem   14(20): 1771-1782 (Journal)
Registered Authors: Schiavone, Marco
Keywords: Inhibitors, calcium, click chemistry, mitochondria, permeability transition pore
MeSH Terms:
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Stability
  • HeLa Cells
  • High-Throughput Screening Assays
  • Humans
  • Isoxazoles/blood
  • Isoxazoles/chemistry
  • Isoxazoles/pharmacology*
  • Mitochondrial Membrane Transport Proteins/antagonists & inhibitors*
  • Mitochondrial Membrane Transport Proteins/metabolism
  • Molecular Structure
  • Muscular Dystrophies/drug therapy*
  • Muscular Dystrophies/metabolism
  • Phenols/blood
  • Phenols/chemistry
  • Phenols/pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Zebrafish
PubMed: 31423734 Full text @ ChemMedChem.
Excessive mitochondrial matrix Ca2+ and oxidative stress leads to the opening of a high-conductance channel of the inner mitochondrial membrane referred to as the mitochondrial permeability transition pore (mtPTP). Because mtPTP opening can lead to cell death under diverse pathophysiological conditions (e.g. ischemia-reperfusion injury and muscular dystrophy), inhibitors of mtPTP are potential therapeutics for various human diseases. High throughput screening efforts led to the identification of a 3-carboxamide-5-phenol-isoxazole compounds as mtPTP inhibitors. While they showed nM potency against mtPTP, they exhibited poor plasma stability, precluding their use in in vivo studies. Herein, we describe a series of structurally related analogs in which the core isoxazole was replaced with a triazole, and this replacement resulted in a substantial improvement in plasma stability. These analogs could be readily generated using the copper-catalyzed "click chemistry". One analog, TR001, was efficacious in a zebrafish model of muscular dystrophy that results from mtPTP dysfunction whereas the isoxazole isostere had minimal effect.