Second-Generation Inhibitors of the Mitochondrial Permeability Transition Pore with Improved Plasma Stability

Justina Šileikytė, Jordan Devereaux, Jelle de Jong, Marco Schiavone, Kristen Jones, Aaron Nilsen, Paolo Bernardi, Michael Forte, Michael S. Cohen

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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, 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 nanomolar potency against mtPTP, they exhibited poor plasma stability, precluding their use in in vivo studies. Herein, we describe a series of structurally related analogues in which the core isoxazole was replaced with a triazole, which resulted in an improvement in plasma stability. These analogues were readily generated using the copper-catalyzed “click chemistry”. One analogue, N-(5-chloro-2-methylphenyl)-1-(4-fluoro-3-hydroxyphenyl)-1H-1,2,3-triazole-4-carboxamide (TR001), was efficacious in a zebrafish model of muscular dystrophy that results from mtPTP dysfunction whereas the isoxazole isostere had minimal effect.

Original languageEnglish (US)
Pages (from-to)1771-1782
Number of pages12
JournalChemMedChem
Volume14
Issue number20
DOIs
StatePublished - Oct 17 2019

Keywords

  • calcium
  • click chemistry
  • inhibitors
  • mitochondria
  • muscular dystrophy
  • permeability transition pore

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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