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MMP inhibitors inactivate matrix metalloproteinases (MMPs).〔J. Frederick, W. (1999). Matrix Metalloproteinase Inhibition: From The Jurassic To The Third Millennium. ''Ann N Y Acad Sci'', 878(1), 388-403. 〕 MMPs belong to a family of zinc-dependent neutral endopeptidases.〔Acharya, M. R., Venitz, J., Figg, W. D., & Sparreboom, A. (2004). Chemically modified tetracyclines as inhibitors of matrix metalloproteinases. Drug Resistance Updates, 7(3), 195-208. doi: http://dx.doi.org/10.1016/j.drup.2004.04.002〕 These enzymes have the ability to break down connective tissue. The expression of MMPs is increased in various pathological conditions like inflammatory conditions, metabolic bone disease, to cancer invasion, metastasis and angiogenesis. Examples of diseases are periodontitis, hepatitis, glomerulonephritis, atherosclerosis, emphysema, asthma, autoimmune disorders of skin and dermal photoaging, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer's disease, chronic ulcerations, uterine involution, bone resorption and tumor progression and metastasis.〔〔Whittaker, Mark., Ayscough, Andrew. (2001). Matrix metalloproteinases and their inhibitors- current status and future challenges. Celltransmissions, 17(1), 3-14〕 Due to the role of MMPs in pathological conditions, inhibitors of MMPs may have therapeutic potential.〔 MMP inhibitors can broadly be subdivided into non-synthetic (e.g. endogenous) or synthetic.〔 Several potent MMP inhibitors have been identified, including hydroxymates, thiols, carbamoylphosphonates, hydroxyureas, hydrazines, β-lactams, squaric acids and nitrogenous ligands.〔Durrant, J. D., de Oliveira, C. A. F., & McCammon, J. A. (2011). Pyrone-Based Inhibitors of Metalloproteinase Types 2 and 3 May Work as Conformation-Selective Inhibitors. Chemical Biology & Drug Design, 78(2), 191-198. 〕 ==History== The first generation of MMP inhibitors were based on the structure of the collagen molecule. This group of inhibitors contain a hydroxamate (-CONHOH) group that binds the zinc atom in the active site of the MMP enzyme.〔Brown, P. D. (1997). Matrix metalloproteinase inhibitors in the treatment of cancer. Medical Oncology, 14 (1), 1-10. 〕 The first MMP inhibitors that were tested in patients were Ilomastat and Batimastat.〔 They are hydroxamate-based MMP inhibitors.〔Fisher, J. F., Mobashery, S. (2006). Recent advances in MMP inhibitor design. Cancer metastasis Rev, 25, 115-136. 〕 Neither compound showed good oral bioavailability.〔 Thus far, Periostat (active ingredient is doxycycline hyclate) is the only MMP inhibitor that has been approved by the U.S. Food and Drug Administration (FDA). It is used for the treatment of periodontitis. Other MMP inhibitors have exhibited serious side effects during preclinical trials. These side effects are caused by insufficient selectivity. Most MMP inhibitors are unable to target specific MMPs connected to specific pathological conditions. Instead they inhibit multiple MMPs, some of which have protective functions or are not related to pathology.〔 MMPs have been regarded as promising targets for cancer therapy. Preclinical studies investigating the efficacy of MMP suppression in tumor models were encouraging. Following these results, clinical studies were conducted but turned out to be disappointing. Recent studies have shown that MMPs may even have paradoxical roles in tumor progression. MMPs seem to have tumor-promoting effects as well as tumor suppressive effects dependent on different contexts.〔Hua, H., Li, M., Luo, T, Yin, Y., Jiang, Y (2011). Matrix Metalloproteinases in Tumorigenesis: an Evolving Paradigm. Cellular and Molecular Life Sciences. 〕 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Discovery and development of matrix metalloproteinase inhibitors」の詳細全文を読む スポンサード リンク
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