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Prodrugs of Phosphonates, Phosphinates, and Phosphates

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Prodrugs

Part of the book series: Biotechnology: Pharmaceutical Aspects ((PHARMASP,volume V))

Abstract

The aim of this chapter is to review the recent progress in the design and development of prodrugs of phosphonate, phosphinate, and phosphate functional groups to improve their physicochemical properties, membrane permeability, oral bioavailability, and drug targeting. Phosphonates, phosphinates, and phosphates are prominently represented as pharmacophores in various classes of biological agents. These include antiviral and anticancer nucleotides, inhibitors of biosynthesis of cholesterol, angiotensin-converting enzyme inhibitors, and bisphosphonates for the treatment of osteoporosis. It is generally well recognized that the therapeutic potential of drugs containing a phosphonate, phosphonate, or phosphate functional group is limited by their inadequate membrane permeation and oral absorption. Phosphonate, phosphinate, and phosphate groups carry one or two negative charges at physiological pH values making them very polar (Figure 1). This high polarity is the basis for many deficiencies in terms of drug delivery. Specifically, ionized species do not readily undergo passive diffusion across cellular membranes. Because of their high polarity, these agents often exhibit a low volume of distribution and, therefore, tend to be subject to efficient renal clearance as well as possibly biliary excretion.

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Authors and Affiliations

  1. Gilead Sciences, Inc., Foster City, CA, 94404

    Gong-Xin He & Reza Oliyai

  2. Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, 66047

    Jeffrey P. Krise

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  1. Gong-Xin He
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  2. Jeffrey P. Krise
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  3. Reza Oliyai
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Editors and Affiliations

  1. University of Kansas, Lawrence, KS, USA

    Valentino J. Stella  & Ronald T. Borchardt  & 

  2. Bristol-Myers Squibb Company, Princeton, NJ, USA

    Michael J. Hageman

  3. Gilead Sciences, Foster City, CA, USA

    Reza Oliyai

  4. Roche Palo Alto, LLC, Palo Alto, CA, USA

    Hans Maag

  5. Hoffmann-La Roche, Inc., Nutley, NJ, USA

    Jefferson W. Tilley

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He, GX., Krise, J.P., Oliyai, R. (2007). Prodrugs of Phosphonates, Phosphinates, and Phosphates. In: Stella, V.J., Borchardt, R.T., Hageman, M.J., Oliyai, R., Maag, H., Tilley, J.W. (eds) Prodrugs. Biotechnology: Pharmaceutical Aspects, vol V. Springer, New York, NY. https://doi.org/10.1007/978-0-387-49785-3_25

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