Matrix metalloproteinases applications

Design and therapeutic application of matrix metalloproteinase heterocyclic inhibitors 99CRV2735. 

Most applications of compounds of this class have been noted during the preceding discussion. The [6,5] fused heterocycle in compound 83 was introduced in one step using a Mitsunobu reaction (Equation 25). This compound, and a number of related structures, showed activity as inhibitors of matrix metalloproteinase <2003JME3840>. 

Originally developed as part of a large-scale effort headed by the United States National Cancer Institute to investigate chemotherapeutic agents from natural sources, paclitaxel was approved by the FDA in 1992 as an antineoplastic agent to treat metastatic ovarian cancer after failure of first-line or subsequent chemotherapy (37). Further studies demonstrated efficacy in other solid tumors (38). In addition, paclitaxel was shown to inhibit T- and B-cell proliferation when tested for transplant-rejection application (39,40) and has demonstrated inhibition of matrix-metalloproteinase synthesis in studies conducted to test its utility for rheumatoid arthritis (41). 

Whittaker M, Floyd CD, Brown P et al (1999) Design and therapeutic application of matrix metalloproteinase inhibitors. Chem Rev 99 2735-2776... 

Skiles JW, Gonnella NC, Jeng AY (2001) The design, structure, and therapeutic application of matrix metalloproteinase inhibitors. Curr Med Chem 8 425-474... 

For assessment of degenerative joint disorders as potential side effects of drugs under investigation, a multitude of animal models for osteoarthritis is available, and their respective suitability for the pleiotropic disease aspects have been recently described and discussed by Oegema and Visco (1999), van den Berg (2001), and Brandt (2002). However, novel therapeutic principles, like e.g. the matrix metalloproteinases, have revealed their musculoskeletal side effects as late as in clinical studies only, which then retraced the focus of drug developmental steps back to scrutinize and refine existent models for different applications (Jacobson et al. 1999 Renkiewicz et al. 2003 Peterson 2004). 

Van Wart, H.E. and Birkedal-Hansen, H. (1990). The cysteine switch A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc. Natl. Acad, Sci. USA 87 5578-5582. 

Many enzymes have been associated with carcinogenesis and metastasis. Elevated levels of certain enzymes may be associated with several different diseases or disorders. The two enzymes that we use in our bioactivity screens, matrix metalloproteinase-3 and caspase-1, have been associated with certain cancers and with certain immune disorders. These enzyme assays will be described relative to both applications. 

MEASUREMENT OF MATRIX METALLOPROTEINASES (MMPS) AND TISSUE INHIBITORS OF METALLOPROTEINASES (TIMP) IN BLOOD AND URINE POTENTIAL CLINICAL APPLICATIONS... 

Considerable interest has evolved over the past decade in the measurement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloprotei-nases (TIMPs) in blood and urine as an aid in the diagnosis and prognosis of disease. The goal of this chapter is to provide a comprehensive review of the subject with the focus on potential future developments and applications of the technology. 

Phlorotannins and Fucoidans from Marine Macroalgae as Matrix Metalloproteinase Inhibitory Substances and Their possible Application as Medicinal Foods... 

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