Inhibitor, Matrix Metalloproteinase development

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

Matrix metalloproteinases (MMPs) are a class of zinc- and calcium-dependent enzymes that are responsible for the metabolism of extracellular matrix proteins [27]. Increased activity of MMPs has been associated with pathological diseases such as arthritis, cancer, multiple sclerosis and Alzheimer s disease [28-31]. Therefore, they constitute an important group of drug targets. Their inhibition is accomplished by blocking the active site of the catalytic domain with ligands that contain hydroxamic or carboxylic acids to chelate the Zn metal. The identification of low molecular weight compounds that contain different scaffolds may lead to the development of a new class of specific inhibitors. 

Hidalgo M, Eckhardt SG, Development of matrix metalloproteinase inhibitors in cancer therapy, J Natl Cancer Inst, 2001 93(3) 178-193. 

The metalloproteases (MPs) and matrix metalloproteinases (MMPs) are a class of metallohydrolases of particular interest to the pharmaceutical industry due to their role in a number of pathological processes [81-83], The lack of an enzyme-bound nucleophilic residue in the metallohydrolases complicates the design of ABPP probes for this class of enzymes. Rather than mechanism-based and electrophilic probes for ABPP, photoreactive variants of reversible inhibitors of metallohydrolases have been developed [84-86]. These reversible inhibitors usually contain a hydroxamate moiety that is capable of chelating the catalytic zinc ion in a bidentate manner [79, 80]. The hydroxamate moiety was incorporated into the first generation of metallohydrolase ABPP probes along with a benzophenone group capable of covalent bond formation upon UV irradiation (Scheme 4). 

The functions of the extracellular matrix are manifold (1.) stabilization of the tissue and organ structure, (2.) structural linkage of cells, (3.) transmission of information between the various types of cells within the tissue and the extracellular milieu, (4.) adhesion or migration of cells, and (5.) influence on the development and differentiation of cells and their polarity. In fibrogenesis, collagen fibres build the framework in which the other components of the extracellular matrix are embedded. In line with this wide scop>e of functions, the extracellular matrix is not only organ-sp>ecific as regards its architecture, but it also displays variations at different locations within the liver, e.g. in Disse s space, in the periportal fields and within the acinus zones. The extracellular matrix is a dynamic structure, i. e. there is a constant equilibrium between build-up (by matrix-metalloproteinases = MMP) and break-down (by tissue inhibitors of matrix metaUoproteinases = TIMP). 

Several experimental studies revealed an early phase of acute tubular necrosis preceding the development of tubular atrophy and interstitial fibrosis [65,68,69]. By using a transgenic mice model, Okada et al demonstrated that hepatocy te growth factor (HGF) did not interfere with the acute phase but reduced the severity of interstitial fibrosis during the tubular regeneration phase, partially through a decreased expression of tissue inhibitor of metalloproteinase-1 and increased matrix metalloproteinase-9 activity [68]. 

Rossello, A., Nuti, E., Catalan , M. P, Carelli, P, Orlandini, E., Rapposelh, S., Tuccinardi, T., Atkinson, S. J., Murphy, G., Balsamo, A. A new development of matrix metalloproteinase inhibitors twin hydroxamic acids as potent inhibitors of MMPs. Bioorg. Med. ChettL Lett. 2005, 75,2311-2314. 

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. 

Ebata, M., Fukuda, Y., Nakano, L, Katano, Y., Fujimoto, N., and Hayakawa, T., Serum levels of tissue inhibitor of metalloproteinases-2 and of precursor form of matrix metalloproteinase-2 in patients with liver disease. Liver 17, 293-299 (1997). Ebihara, L, Nakamura, T., Shimada, N., and Koide, H., Increased plasma metalloproteinase-9 concentrations precede development of microalbuminuria in non-insulin-dependent diabetes mellitus. Am. J. Kidney Dis. 32, 544-550 (1998). 

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