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Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo

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journal contribution
posted on 26.06.2014, 00:00 authored by Daniele Fancelli, Agnese Abate, Raffaella Amici, Paolo Bernardi, Marco Ballarini, Anna Cappa, Giacomo Carenzi, Andrea Colombo, Cristina Contursi, Fabio Di Lisa, Giulio Dondio, Stefania Gagliardi, Eva Milanesi, Saverio Minucci, Gilles Pain, Pier Giuseppe Pelicci, Alessandra Saccani, Mariangela Storto, Florian Thaler, Mario Varasi, Manuela Villa, Simon Plyte
In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.