TY - JOUR
T1 - Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo
AU - Fancelli, Daniele
AU - Abate, Agnese
AU - Amici, Raffaella
AU - Bernardi, Paolo
AU - Ballarini, Marco
AU - Cappa, Anna
AU - Carenzi, Giacomo
AU - Colombo, Andrea
AU - Contursi, Cristina
AU - Di Lisa, Fabio
AU - Dondio, Giulio
AU - Gagliardi, Stefania
AU - Milanesi, Eva
AU - Minucci, Saverio
AU - Pain, Gilles
AU - Pelicci, Pier Giuseppe
AU - Saccani, Alessandra
AU - Storto, Mariangela
AU - Thaler, Florian
AU - Varasi, Mario
AU - Villa, Manuela
AU - Plyte, Simon
PY - 2014/6/26
Y1 - 2014/6/26
N2 - 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.
AB - 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.
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U2 - 10.1021/jm500547c
DO - 10.1021/jm500547c
M3 - Article
C2 - 24918261
AN - SCOPUS:84903535395
VL - 57
SP - 5333
EP - 5347
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 12
ER -