Novel analogues of istaroxime, a potent inhibitor of Na+,K+-ATPase:: Synthesis and structure-activity relationship
Novel analogues of istaroxime, a potent inhibitor of Na+,K+-ATPase:: Synthesis and structure-activity relationship
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DOI：
10.1021/jm800257s
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发表时间：
2008-08-14
影响因子：
7.3
通讯作者：
Cerri, Alberto
中科院分区：
文献类型：
--
作者：
Gobbini, Mauro;Armaroli, Silvia;Cerri, Alberto
我们报道了作为正性肌力化合物的新型Na+，K+-ATPase抑制剂的合成和生物学性质。按照我们之前描述的生成Istaroxime的模型，5α，14α雄烷骨架被用作支架来研究我们的先导化合物基本链周围的空间。一些化合物在受体上表现出比Istarime更高的效价，其中(E)-3-[(R)-3-吡咯烷基]肟衍生物，15，是最有效的；进一步证实了我们的模型，肟的E异构体比Z型更有效。在豚鼠模型中测试的化合物具有正性变力作用，这与其对Na+，K+-ATPase的体外抑制作用有关。这一发现表明，所有被测试的化合物都比目前临床上使用的正性肌力药地高辛诱发心律失常的作用要小，这表明这可能是5α，14α雄烷烷的3-氨基烷酮衍生物类的一个特征。
We report the synthesis and biological properties of novel inhibitors of the Na+,K+-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5 alpha,14 alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na+,K+-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5 alpha,14 alpha-androstane.