ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice
ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice
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DOI：
10.1182/blood-2002-05-1433
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发表时间：
2003-03-15
期刊：
影响因子：
20.3
通讯作者：
Brugnara, C
中科院分区：
文献类型：
--
作者：
Stocker, JW;De Franceschi, L;Brugnara, C
镰状细胞性贫血的一个显着特征是循环中存在脱水红细胞（RBC）。红细胞中钾 (K+)、氯 (Cl-) 和水的损失被认为有助于产生这些脱水细胞。红细胞中 K+ 损失的一个主要途径是 Gardos 通道，一种钙 (Ca2+) 激活的 K+ 通道。克霉唑 (CLT) 是一种 Gardos 通道抑制剂，已被证明可以在体外和体内减少红细胞脱水。我们开发了一种化学新颖化合物 ICA-17043，在抑制 Gardos 通道方面比 CLT 具有更大的效力和选择性。 ICA-17043 阻断 Ca2+ 诱导的人红细胞铷通量，IC50 值为 11+/-2 nM (CLT IC50=100+/-12 nM)，并抑制红细胞脱水，IC50 为 30+/-20 nM。在镰状细胞病 (SAD) 转基因小鼠模型中，用 ICA-17043（口服 10 mg/kg，每天两次）治疗 21 天，显示出对 Gardos 通道活性的显着且持续的抑制（平均抑制率为 90% +/-27%，P
A prominent feature of sickle cell anemia is the presence of dehydrated red blood cells (RBCs) in circulation. Loss of potassium (K+), chloride (Cl-), and water from RBCs is thought to contribute to the production of these dehydrated cells. One main route of K+ loss in the RBC is the Gardos channel, a calcium (Ca2+)-activated K+ channel. Clotrimazole (CLT), an inhibitor of the Gardos channel, has been shown to reduce RBC dehydration in vitro and in vivo. We have developed a chemically novel compound, ICA-17043, that has greater potency and selectivity than CLT in inhibiting the Gardos channel. ICA-17043 blocked Ca2+-induced rubidium flux from human RBCs with an IC50 value of 11+/-2 nM (CLT IC50=100+/-12 nM) and inhibited RBC dehydration with an IC50 of 30+/-20 nM. In a transgenic mouse model of sickle cell disease (SAD), treatment with ICA-17043 (10 mg/kg orally, twice a day) for 21 days showed a marked and constant inhibition of the Gardos channel activity (with an average inhibition of 90% +/-27%, P