Novel carvedilol analogues that suppress store-overload-induced Ca2+ release.
Novel carvedilol analogues that suppress store-overload-induced Ca2+ release.
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DOI：
10.1021/jm401090a
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发表时间：
2013-11-14
影响因子：
7.3
通讯作者：
Back TG
中科院分区：
文献类型：
--
作者：
Smith CD;Wang A;Vembaiyan K;Zhang J;Xie C;Zhou Q;Wu G;Chen SR;Back TG
卡维地洛是治疗心力衰竭患者心律失常的独特有效药物。这种活性部分是由于其通过RyR 2通道抑制储存过载诱导的钙释放（SOICR）的能力。我们描述了ca的合成，表征和生物测定。基于卡维地洛基序的100种化合物，以鉴定与SOICR抑制相关并优化SOICR抑制的特征。基于RyR 2-R4496 C突变体HEK-293细胞系采用单细胞生物测定，其中测量通过缺陷通道从内质网释放的钙。由此获得SOICR抑制的IC 50值。所研究的化合物含有对卡维地洛的三个主要亚基的修饰，包括咔唑和儿茶酚部分，以及含有β-氨基醇官能团的连接链。SAR结果表明，在这三个亚基中的每一个中，显著的改变是耐受的。
Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part due to its ability to inhibit store overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization and bioassay of ca. 100 compounds based on the carvedilol motif in order to identify features that correlate with and optimize SOICR inhibition. A single cell bioassay was employed based on the RyR2-R4496C mutant HEK-293 cell line, in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the β-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.
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影响因子：
15.9
作者：
MARBAN, E;ROBINSON, SW;WIER, WG
通讯作者：
WIER, WG
影响因子：
20.1
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Cerrone, M;Colombi, B;Priori, SG
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Priori, SG
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