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 Forte, Paolo Bernardi, Frank J. Schoenen

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 (EC5050>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

Fingerprint

Isoxazoles
Muscular Dystrophies
Zebrafish
Cell death
Cell Death
Mitochondrial Swelling
Mitochondria
Pathology
Swelling
Cause of Death
Assays
Collagen
mitochondrial permeability transition pore
Calcium
Molecules
Therapeutics
Pharmaceutical Preparations
N-(3-chloro-2-methylphenyl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

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

Cite this

Roy, S., Šileikyte, J., Schiavone, M., Neuenswander, B., Argenton, F., Aubé, J., ... 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

Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. / Roy, Sudeshna; Šileikyte, Justina; Schiavone, Marco; Neuenswander, Benjamin; Argenton, Francesco; Aubé, Jeffrey; Hedrick, Michael P.; Chung, Thomas D Y; Forte, Michael; Bernardi, Paolo; Schoenen, Frank J.

In: ChemMedChem, Vol. 10, No. 10, 01.10.2015, p. 1655-1671.

Research output: Contribution to journalArticle

Roy, S, Šileikyte, J, Schiavone, M, Neuenswander, B, Argenton, F, Aubé, J, Hedrick, MP, Chung, TDY, Forte, M, Bernardi, P & Schoenen, FJ 2015, 'Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore', ChemMedChem, vol. 10, no. 10, pp. 1655-1671. https://doi.org/10.1002/cmdc.201500284
Roy, Sudeshna ; Šileikyte, Justina ; Schiavone, Marco ; Neuenswander, Benjamin ; Argenton, Francesco ; Aubé, Jeffrey ; Hedrick, Michael P. ; Chung, Thomas D Y ; Forte, Michael ; Bernardi, Paolo ; Schoenen, Frank J. / Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. In: ChemMedChem. 2015 ; Vol. 10, No. 10. pp. 1655-1671.
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