Zinc-binding groups modulate selective inhibition of MMPs
Zinc-binding groups modulate selective inhibition of MMPs
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DOI：
10.1002/cmdc.200700290
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发表时间：
2008-05-01
期刊：
影响因子：
3.4
通讯作者：
Cohen, Seth M.
中科院分区：
文献类型：
--
作者：
Agrawal, Arpita;Romero-Perez, Diego;Cohen, Seth M.
由于不同的基质金属蛋白酶亚型介导了不同的病理过程，选择性抑制基质金属蛋白酶的必要性引起了人们的兴趣。更具选择性的基质金属蛋白酶抑制剂(MMPI)的开发可能有助于克服一些阻碍这些化合物临床成功的不良副作用。为了设计新的选择性抑制剂的方法，我们在这里描述了几种新的MMPI，并表明它们的选择性取决于锌结合基团(ZBG)的性质。这与目前大多数MMPI相反，MMPI仅从化合物的模拟肽骨架部分获得异构体选择性。在本研究中，将六种不同的羟基吡喃酮和羟基吡二酮ZBG添加到一个共同的联苯骨架上，并在体外测定了每个抑制剂对基质金属蛋白酶-1、-2、-3、-7、-8、1-9、-12和-13的抑制效率(IC(50)值)。结果表明，不同的ZBG对不同缓蚀剂的选择性有不同的影响。计算模型研究被用来解释观察到的选择性分布的一些趋势。为了评估ZBG在生物模型中的重要性，我们用一只隔离的大鼠心脏系统评估了两种半选择性、有效的MMPI(和一种对照)。采用心脏缺血再灌注损伤模型，观察心脏收缩功能的恢复情况。在该模型中，两种MMPI中只有一种表现出显著和持续的心脏恢复，表明选择ZBG可以对相关的病理生理终点产生显著影响。
The need for selective matrix metalloproteinase (MMP) inhibition is of interest because of the range of pathologies mediated by different MMP isoforms. The development of more selective MMP inhibitors (MMPi) may help to overcome some of the undesired side effects that have hindered the clinical success of these compounds. In on effort to devise new approaches to selective inhibitors, herein we describe several novel MMPi and show that their selectivity is dependent on the nature of the zinc-binding group (ZBG). This is in contrast to most current MMPi, which obtain isoform selectivity solely from the peptidomimetic backbone portion of the compound. In the present study, six different hydroxypyrone and hydroxypyridinone ZBGs were appended to a common biphenyl backbone and the inhibition efficiency of each inhibitor was determined in vitro (IC(50) values) against MMP-1, -2, -3, -7, -8, 1 -9, -12, and -13. The results show that the selectivity profile of each inhibitor is different as a result of the various ZBGs. Computational modeling studies were used to explain some trends in the observed selectivity profiles. To assess the importance of the ZBG in a biological model, two of the semiselective, potent MMPi (and one control) were evaluated using an isolated perfused rat 1; heart system. Hearts were subjected to ischemia reperfusion injury, and recovery of contractile function was examined. In this model, only one of the two MMPi showed significant and sustained heart recovery, demonstrating that the choice of ZBG can have a significant effect in a relevant pathophysiological endpoint.