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

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

  • ChemMedChem. 2015 Oct;10(10):1655-71. doi: 10.1002/cmdc.201500284.
Sudeshna Roy 1,  Justina Šileikytė 2,  Marco Schiavone 2,  Benjamin Neuenswander 1,  Francesco Argenton 3,  Jeffrey Aubé 1,  Michael P Hedrick 4,  Thomas D Y Chung 4,  Michael A Forte 5,  Paolo Bernardi 6,  Frank J Schoenen 7
Affiliations

Affiliations

  • 1 University of Kansas Specialized Chemistry Center, 2304 Becker Drive, Lawrence, KS 66049 (USA).
  • 2 CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Padova, 35131 (Italy).
  • 3 Department of Biology, University of Padova, Padova, 35131 (Italy).
  • 4 Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037 (USA).
  • 5 Vollum Institute, Oregon Health & Science University, Portland, OR 97239 (USA). forte@ohsu.edu.
  • 6 CNR Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Padova, 35131 (Italy). bernardi@bio.unipd.it.
  • 7 University of Kansas Specialized Chemistry Center, 2304 Becker Drive, Lawrence, KS 66049 (USA). schoenen@ku.edu.
PMID: 26286375 DOI: 10.1002/cmdc.201500284
Abstract

The mitochondrial permeability transition pore (mtPTP) is a CA(2+) -requiring mega-channel which, under pathological conditions, leads to the deregulated release of CA(2+) 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.

Keywords

calcium retention capacity; mitochondria; muscular dystrophy; permeability transition; zebrafish.

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