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dc.contributor.authorRoy, Sudeshna
dc.contributor.authorŠileikytė, Justina
dc.contributor.authorSchiavone, Marco
dc.contributor.authorNeuenswander, Benjamin
dc.contributor.authorArgenton, Francesco
dc.contributor.authorAubé, Jeffrey
dc.contributor.authorHendrick, Michael P.
dc.contributor.authorChung, Thomas D. Y.
dc.contributor.authorForte, Michael A.
dc.contributor.authorBernardi, Paolo
dc.contributor.authorSchoenen, Frank J.
dc.date.accessioned2017-05-08T18:23:15Z
dc.date.available2017-05-08T18:23:15Z
dc.date.issued2015-10
dc.identifier.citationRoy, S., Šileikytė, 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. http://doi.org/10.1002/cmdc.201500284en_US
dc.identifier.urihttp://hdl.handle.net/1808/24018
dc.descriptionThis is the peer reviewed version of the following article: Roy, S., Šileikytė, 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. http://doi.org/10.1002/cmdc.201500284, which has been published in final form at doi.org/10.1002/cmdc.201500284. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.en_US
dc.description.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 (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.en_US
dc.publisherWileyen_US
dc.rights© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheimen_US
dc.subjectCalcium retention capacityen_US
dc.subjectMitochondriaen_US
dc.subjectMuscular dystrophyen_US
dc.subjectPermeability transitionen_US
dc.subjectZebrafishen_US
dc.titleDiscovery, Synthesis, and Optimization of Diarylisoxazole-3- carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Poreen_US
dc.typeArticleen_US
kusw.kuauthorRoy, Sudeshna
kusw.kuauthorNeuenswander, Benjamin
kusw.kuauthorAubé, Jeffrey
kusw.kuauthorSchoenen, Frank
kusw.kudepartmentHiguchi Biosciences Centeren_US
dc.identifier.doi10.1002/cmdc.201500284en_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC4674087en_US
dc.rights.accessrightsopenAccess


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