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Hydroxamic Acid Matrix Metalloproteinase Inhibitors

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Book cover Matrix Metalloproteinase Inhibitors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

It is now apparent that the matrix metalloproteinases (MMPs) play a key role in the remodeling of basement membrane that is associated with tumor metastasis, growth, and angiogenesis. Thus there is considerable interest in the design of MMP inhibitors (MMPIs) (1–6) as they promise to provide a novel noncytotoxic means of treating human cancer. Furthermore, pharmacological studies of MMPIs in animal models of human disease suggest that the potential therapeutic applications will encompass other endpoints such as arthritis and multiple-sclerosis. Recently, evidence has shown that MMP inhibitors can also reduce the production of TNF-α by inhibiting a TNF-α converting enzyme (TACE) (7–9). As a consequence, this “dual activity” may be of benefit in diseases which involve both inflammation and matrix remodeling. In this chapter we review the hydroxamic acid class of MMPIs with specific reference to the research program at British Biotech and the compounds batimastat 1 (BB-94) and marimastat 2 (BB-2516) (Fig. 1). Batimastat was the first MMPI to enter human clinical trials in cancer patients. This compound has been superseded by the orally active MMPI marimastat which is now under Phase III clinical evaluation in late-stage cancer patients. Here we present an overview of the medicinal chemistry relating to batimastat and marimastat, discuss the preclinical evaluation of compounds of this class in animal models of cancer and other human diseases and review the current clinical status for marimastat.

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Authors
  1. Peter D. Brown DPhil
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  2. Alan H. Davidson MA, PhD
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  3. Alan H. Drummond PhD
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  4. Andrew Gearing PhD
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  5. Mark Whittaker DPhil
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Editors and Affiliations

  1. Corporate V.P., Clinical Affairs, Agouron Pharmaceuticals Inc., San Diego, CA, USA

    Neil J. Clendeninn MD, PhD

  2. Department of Research Pharmacology, Agouron Pharmaceuticals Inc., San Diego, CA, USA

    Krzysztof Appelt PhD

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Brown, P.D., Davidson, A.H., Drummond, A.H., Gearing, A., Whittaker, M. (2001). Hydroxamic Acid Matrix Metalloproteinase Inhibitors. In: Clendeninn, N.J., Appelt, K. (eds) Matrix Metalloproteinase Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-011-7_5

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  • DOI: https://doi.org/10.1007/978-1-59259-011-7_5

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-123-3

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