Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

Sudeshna Roy, Justina Šileikyte, Marco Schiavone, Benjamin Neuenswander, Francesco Argenton, Jeffrey Aubé, Michael P. Hedrick, Thomas D.Y. Chung, Michael A. Forte, Paolo Bernardi, Frank J. Schoenen

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The mitochondrial permeability transition pore (mtPTP) is a Ca2+-requiring mega-channel which, under pathological conditions, leads to the deregulated release of Ca2+ and mitochondrial dysfunction, ultimately resulting in cell death. Although the mtPTP is a potential therapeutic target for many human pathologies, its potential as a drug target is currently unrealized. Herein we describe an optimization effort initiated around hit 1, 5-(3-hydroxyphenyl)-N-(3,4,5-trimethoxyphenyl)isoxazole-3-carboxamide, which was found to possess promising inhibitory activity against mitochondrial swelling (EC50<0.39 μM) and showed no interference on the inner mitochondrial membrane potential (rhodamine 123 uptake EC50>100 μM). This enabled the construction of a series of picomolar mtPTP inhibitors that also potently increase the calcium retention capacity of the mitochondria. Finally, the therapeutic potential and in vivo efficacy of one of the most potent analogues, N-(3-chloro-2-methylphenyl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide (60), was validated in a biologically relevant zebrafish model of collagen VI congenital muscular dystrophies. Stop the pore: Prolonged Ca2+-dependent opening of the mitochondrial permeability transition pore (mtPTP) causes cell death. Herein we describe the discovery of novel small-molecule mtPTP inhibitors with picomolar activity in in vitro assays and high in vivo efficacy in a zebrafish model of muscular dystrophies.

Original languageEnglish (US)
Pages (from-to)1655-1671
Number of pages17
JournalChemMedChem
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2015

Keywords

  • calcium retention capacity
  • mitochondria
  • muscular dystrophy
  • permeability transition
  • zebrafish

ASJC Scopus subject areas

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

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    Roy, S., Šileikyte, J., Schiavone, M., Neuenswander, B., Argenton, F., Aubé, J., Hedrick, M. P., Chung, T. D. Y., Forte, M. A., Bernardi, P., & Schoenen, F. J. (2015). Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem, 10(10), 1655-1671. https://doi.org/10.1002/cmdc.201500284