Prodrugs pp 923-964 | Cite as

Prodrugs of Phosphonates, Phosphinates, and Phosphates

  • Gong-Xin He
  • Jeffrey P. Krise
  • Reza Oliyai
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)


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.


Oral Bioavailability Tenofovir Disoproxil Fumarate Adefovir Dipivoxil Etidronic Acid Ester Prodrug 


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Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Gong-Xin He
    • 1
  • Jeffrey P. Krise
    • 2
  • Reza Oliyai
    • 1
  1. 1.Gilead Sciences, Inc.Foster City
  2. 2.Department of Pharmaceutical ChemistryThe University of KansasLawrence

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