Sodium late current blockers in ischemia reperfusion: Is the bullet magic?
Sodium late current blockers in ischemia reperfusion: Is the bullet magic?
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DOI：
10.1021/jm800100z
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发表时间：
2008-07-10
影响因子：
7.3
通讯作者：
Vacher, Bernard
中科院分区：
文献类型：
--
作者：
Le Grand, Bruno;Pignier, Christophe;Vacher, Bernard
我们描述了第一个选择性的，有效的，电压依赖性的抑制剂的心脏钠通道Na（V）1.5介导的晚电流的发现。化合物3，4-二氢-N-[（2S）-3-[（2-甲氧苯基）硫基]-2-甲基丙基]-2H-（3R）-1，5-苯并氧硫杂卓-3-胺，2a（F 15845）是从一个新的3-氨基-1，5-苯并氧硫杂卓衍生物家族中鉴定出来的。在各种离体和体内模型中研究了2a的迟发钠电流抑制和抗缺血作用。在兔缺血再灌注模型中，2a表现出比参比化合物KC 12291、雷诺嗪和伊伐布雷定更有效的抗缺血作用。因此，单次给药后，2a几乎消除了ST段抬高对短暂冠状动脉闭塞的反应。此外，与常规抗缺血剂相反，2a的抗缺血活性在宽剂量范围内保持，并且与任何血液动力学变化无关。2a独特的药理学特性为缺血性心脏病的治疗开辟了新的和有希望的机会。
We describe the discovery of the first selective, potent, and voltage-dependent inhibitor of the late current mediated by the cardiac sodium channel Na(V)1.5. The compound 3,4-dihydro-N-[(2S)-3-[(2-methoxyphenyl)thio]-2-methylpropyll-2H-(3R)-1,5-benzoxathiepin-3-amine, 2a (F 15845), was identified from a novel family of 3-amino-1,5-benzoxathiepine derivatives. The late sodium current inhibition and antiischemic effects of 2a were studied in various models in vitro and in vivo. In a rabbit model of ischemia-reperfusion, 2a exhibited more potent antiischemic effects than reference compounds KC 12291, ranolazine, and ivabradine. Thus, after a single administration, 2a almost abolished ST segment elevation in response to a transient coronary occlusion. Further, the antiischemic activity of 2a is maintained over a wide range of doses and is not associated with any hemodynamic changes, contrary to conventional antiischemic agents. The unique pharmacological profile of 2a opens new and promising opportunities for the treatment of ischemic heart diseases.