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

dc.contributor.authorRoy, Sudeshnaen
dc.contributor.authorŠileikytė, Justinaen
dc.contributor.authorSchiavone, Marcoen
dc.contributor.authorNeuenswander, Benjaminen
dc.contributor.authorArgenton, Francescoen
dc.contributor.authorAubé, Jeffreyen
dc.contributor.authorHedrick, Michael P.en
dc.contributor.authorChung, Thomas D. Y.en
dc.contributor.authorForte, Michael A.en
dc.contributor.authorBernardi, Paoloen
dc.contributor.authorSchoenen, Frank J.en
dc.creatorRoy, Sudeshnaen
dc.creatorŠileikytė, Justinaen
dc.creatorSchiavone, Marcoen
dc.creatorNeuenswander, Benjaminen
dc.creatorArgenton, Francescoen
dc.creatorAubé, Jeffreyen
dc.creatorHedrick, Michael P.en
dc.creatorChung, Thomas D. Y.en
dc.creatorForte, Michael A.en
dc.creatorBernardi, Paoloen
dc.creatorSchoenen, Frank J.en
dc.date.accessioned2019-11-21T06:22:40Z
dc.date.available2019-11-21T06:22:40Z
dc.date.issued2015
dc.identifier.urihttp://gnosis.library.ucy.ac.cy/handle/7/56099
dc.source.urihttps://nls.ldls.org.uk/welcome.html?ark:/81055/vdc_100026597833.0x00003c
dc.subjectPharmaceutical chemistryen
dc.titleDiscovery, Synthesis, and Optimization of Diarylisoxazole‐3‐carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Poreen
dc.typeinfo:eu-repo/semantics/article
dc.author.faculty002 Σχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied Sciences
dc.author.departmentΤμήμα Χημείας / Department of Chemistry
dc.type.uhtypeArticleen
dc.description.notes<p>ID: 1193en
dc.description.notesIn: ChemMedChem, Vol. 10, no. 10 (Oct. 2015), p.1655-1671.en
dc.description.notesSummary: AbstractThe 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 (EC50100 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.</p>en


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