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Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo
journal contribution
posted on 2014-06-26, 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 PlyteIn
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.
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rabbit modelseriesInitial class expansionlimit reperfusion injurycalcium overloadNew Mitochondrial Permeability Transition Pore Inhibitors Endowedvivo dataCsAcinnamic anilidesattenuate openingnovel classcompoundCinnamic Anilidescinnamic anilide mPTP inhibitorsmPTP openingoxidative stressmitochondrial permeability transition pore
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