Laboratory for Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, K.U. Leuven, Herestraat 49 PB 923, B-3000 Leuven, Belgium.
Curr Drug Metab. 2011 May;12(4):395-410. doi: 10.2174/138920011795202901.
Enzymes are major drug targets in drug discovery and development processes in the pharmaceutical and biotechnology industry. A recent survey found that nearly half of all the marketed small-molecule drugs are inhibitors of enzymes. Matrix metalloproteinases (MMPs) are a family of 28 enzymes capable of degrading the constituents of the extracellular matrix (ECM) and the basement-membrane. MMPs play an essential role in several normal physiological processes including growth, wound healing and tissue repair. Over-expression and activation of MMPs has been linked to a range of diseases which include osteoarthritis, tumor metastasis, angiogenesis and cardiovascular diseases. The development of MMP inhibitors as therapeutic agents has kept an important place in drug discovery. Therefore, there is also an increasing need for robust analytical methods for evaluation of inhibitory potency and for the analysis of MMP inhibitors and their metabolites which can even play a more significant role than the parent drug. Modern analytical techniques and hyphenated instrumentations such as liquid chromatography-mass spectrometry with a function of structure elucidation can provide a profound insight into the research of MMP inhibitors and also serve as a complementary method to zymographic techniques for the analysis of biological samples. This review mainly summarizes bioanalytical methods, pharmacokinetics and related metabolites of MMP inhibitors over the last 12 years.
酶是药物发现和开发过程中制药和生物技术行业的主要药物靶点。最近的一项调查发现，近一半的上市小分子药物都是酶的抑制剂。基质金属蛋白酶（MMPs）是能够降解细胞外基质（ECM）和基底膜成分的 28 种酶家族。MMPs 在包括生长、伤口愈合和组织修复在内的几种正常生理过程中发挥着重要作用。MMPs 的过度表达和激活与一系列疾病有关，包括骨关节炎、肿瘤转移、血管生成和心血管疾病。作为治疗剂的 MMP 抑制剂的开发在药物发现中占有重要地位。因此，也越来越需要用于评估抑制效力以及分析 MMP 抑制剂及其代谢物的强大分析方法，这些方法甚至可以比母体药物发挥更重要的作用。现代分析技术和联用仪器，如具有结构解析功能的液相色谱-质谱联用技术，可以深入了解 MMP 抑制剂的研究，也可以作为酶谱技术的补充方法，用于分析生物样品。本文主要综述了过去 12 年 MMP 抑制剂的生物分析方法、药代动力学和相关代谢物。
