Ongoing trials with matrix metalloproteinase inhibitors
Ongoing trials with matrix metalloproteinase inhibitors
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DOI：
10.1517/13543784.9.9.2167
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发表时间：
2000-09-01
影响因子：
6.1
通讯作者：
Brown, PD
中科院分区：
文献类型：
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作者：
Brown, PD
基质金属蛋白酶(MMPs)活性过高或调节不良是一系列疾病的致病因素，在这些疾病中细胞外基质降解或重塑。合成的、有效的、低分子的基质金属蛋白酶抑制剂(MMPI)已经被开发出来，在过去的五年里，这些药物已经开始在癌症、类风湿性关节炎、骨关节炎和急性黄斑变性患者中进行临床测试。在过去的一年里，随着Ro 32-3555和Bay 12-9566在类风湿性关节炎患者和癌症患者的临床试验的停止，我们看到了一些令人失望的事情。然而，已经有了一些成功的结果，也许最昂贵的疗效迹象是在进展期胃癌患者的马拉马特第三阶段试验结果中看到的。Marimastat和其他MMPIs的临床试验仍在继续，包括Priromastat、Solimastat、EMS275291、MetaStat和neovastat。这些试验的结果预计将在未来两年内公布，MMPIs的临床试验很可能将在其他疾病患者中开始，这些疾病据信涉及MMPs，如再狭窄、脑出血和多发性硬化症。未来的研究可能集中在识别不同疾病中特定的基质金属蛋白酶靶点，以提高疗效并减少肌肉骨骼副作用，这些副作用是第一代口服MMPI的特征。
Excessive or poorly regulated matrix metalloproteinase (MMP) activity has been implicated as a pathogenic factor in a range of diseases where the extracellular matrix is degraded or remodelled. Synthetic, potent, low molecular weight MMP inhibitors (MMPIs) have been developed and, over the past five years, these agents have begun clinical testing in patients with cancer, rheumatoid arthritis, osteoarthritis and acute macular degeneration. The past year has seen a number of disappointments with the halting of clinical trials of Ro 32-3555 in patients with rheumatoid arthritis and of BAY 12-9566 in patients with cancer. There have, however, been some successes with perhaps the dearest indication of efficacy being seen in the results of a Phase III trial of marimastat in patients with advanced gastric cancer. Clinical trials are continuing with marimastat and other MMPIs, including prinomastat, solimastat, EMS 275291, metastat and neovastat. Results from these trials are expected in the next two years and it is likely that clinical trials with MMPIs will begin in patients with other diseases where MMPs are believed to be involved, such as restenosis, cerebral haemorrhage and multiple sclerosis. Future research is likely to focus on the identification of specific MMP targets in different diseases, both in order to improve efficacy and to reduce the musculoskeletal side effect profile that has characterised several of the first generation oral MMPIs.