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

被引：64

作者：

Fancelli, Daniele ^{[1
]}

Abate, Agnese ^{[2
]}

Amici, Raffaella ^{[1
]}

Bernardi, Paolo ^{[5
]}

Ballarini, Marco ^{[1
,3
]}

Cappa, Anna ^{[2
]}

Carenzi, Giacomo ^{[2
]}

Colombo, Andrea ^{[7
]}

Contursi, Cristina ^{[1
]}

Di Lisa, Fabio ^{[6
]}

Dondio, Giulio ^{[7
]}

Gagliardi, Stefania ^{[7
]}

Milanesi, Eva ^{[1
]}

Minucci, Saverio ^{[3
,4
]}

Pain, Gilles ^{[1
]}

Pelicci, Pier Giuseppe ^{[3
]}

Saccani, Alessandra ^{[1
]}

Storto, Mariangela ^{[1
,3
]}

Thaler, Florian ^{[1
]}

Varasi, Mario ^{[2
]}

Villa, Manuela ^{[1
]}

Plyte, Simon ^{[1
]}

机构：

[1] Congenia Srl, Genextra Grp, I-20139 Milan, Italy

[2] DAC Srl, Genextra Grp, I-20139 Milan, Italy

[3] IEO, Dept Expt Oncol, I-20139 Milan, Italy

[4] Univ Milan, Dept Biosci, I-20100 Milan, Italy

[5] Univ Padua, Dept Biomed Sci, I-35121 Padua, Italy

[6] Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy

[7] NiKem Res Srl, I-20021 Baranzate Di Bollate, MI, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 12期

关键词：

ACUTE MYOCARDIAL-INFARCTION; CYCLOPHILIN INHIBITOR; CYCLOSPORINE-A; MUSCLE; MODEL;

D O I：

10.1021/jm500547c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-hydroxyphenyl)-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.

引用

页码：5333 / 5347

页数：15

共 36 条

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