First-in-class pan caspase inhibitor developed for the treatment of liver disease
First-in-class pan caspase inhibitor developed for the treatment of liver disease
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DOI：
10.1021/jm050307e
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发表时间：
2005-11-03
影响因子：
7.3
通讯作者：
Zhang, CZ
中科院分区：
文献类型：
--
作者：
Linton, SD;Aja, T;Zhang, CZ
一系列杀线酰二肽针对泛胱天蛋白酶抑制、抗凋亡细胞活性和体内功效进行了优化。本构效关系研究集中在P4草酰胺和弹头部分。首先基于体外数据，选择抑制剂用于在α-Fas诱导的肝损伤的鼠模型中进行研究。在其他体内模型和药代动力学研究中进一步分析了IDN-6556（1）。这种一流的半胱天冬酶抑制剂现在是两项11期临床试验的主题，评估其用于肝病的安全性和有效性。
A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase 11 clinical trials, evaluating its safety and efficacy for use in liver disease.