Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo
Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo
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DOI：
10.1021/jm500547c
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发表时间：
2014-06-26
影响因子：
7.3
通讯作者：
Plyte, Simon
中科院分区：
文献类型：
--
作者：
Fancelli, Daniele;Abate, Agnese;Plyte, Simon
在这个帐户中，我们报告了一系列的取代肉桂酰苯胺，代表一类新的线粒体通透性转换孔（mPTP）抑制剂的发展。最初的类扩展导致建立的基本结构要求的活动和鉴定的衍生物的抑制效力高于标准的抑制剂环孢菌素A（CsA）。这些化合物可以抑制mPTP开放响应于几种刺激，包括钙超载，氧化应激，和硫醇交联剂。肉桂酰苯胺mPTP抑制剂的活性与CsA的活性相加，表明这些抑制剂的分子靶点不同于cyclophylin-D。提供了（E）-3-（4-氟-3-羟基苯基）-N-萘-1-基-丙烯酰胺22的体外和体内数据，（E）-3-（4-氟-3-羟基苯基）-N-萘-1-基-丙烯酰胺22是该系列中最令人感兴趣的化合物之一，能够在急性心肌梗死的兔模型中减弱mPTP的开放并限制再灌注损伤。
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.