Designing Safer (Soft) Drugs by Avoiding the Formation of Toxic and Oxidative Metabolites

  • Nicholas Bodor
  • Peter Buchwald
Part of the Methods in Molecular Biology™ book series (MIMB, volume 186)


Living organisms possess not only fine-tuned metabolic mechanisms for endogenous chemicals but also several defensive mechanisms to detoxify xenobiotics. Most metabolic processes that eliminate invading foreign chemicals by transforming them into more hydrophilic or more easily conjugated compounds are oxidative in nature. Unfortunately, many of these mechanisms are indiscriminate, and detoxifying enzymes, such as cytochrome P450 or N-acetyltransferase, can generate toxic reactive intermediates such as epoxides or radicals from otherwise nontoxic compounds (1,2). Chemicals and xenobiotics, therefore, are not always metabolized only into more hydrophilic and less toxic substances, but also into highly reactive chemical species, which then can react with various macromolecules and cause tissue damage or elicit antigen production.


Inactive Metabolite Oxidative Metabolite Soft Chemical Nontoxic Compound Carboxylic Ester Hydrolase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Gillette, J. R. (1979) Effects of induction of cytochrome P-450 enzymes on the concentration of foreign compounds and their metabolites and on the toxicological effects of these compounds. Drug Metab. Rev. 10, 59–87.CrossRefPubMedGoogle Scholar
  2. 2.
    Picot, A. and Macherey, A.-C. (1996) Chemical aspects of biotransformations leading to toxic metabolites, in The Practice of Medicinal Chemistry (Wermuth, C. G., ed.), Academic Press, London, pp. 643–670.Google Scholar
  3. 3.
    Mannering, G. J. (1981) Hepatic cytochrome P-450-linked drug-metabolizing systems, in Concepts in Drug Metabolism Part B (Testa, B. and Jenner, P., eds.), Marcel Dekker, New York, pp. 53–166.Google Scholar
  4. 4.
    Leinweber, F.-J. (1987) Possible physiological roles of carboxylic ester hydrolases. Drug Metab. Rev. 18, 379–439.CrossRefPubMedGoogle Scholar
  5. 5.
    Satoh, T. and Hosokawa, M. (1998) The mammalian carboxylesterases: from molecules to functions. Annu. Rev. Pharmacol. Toxicol. 38, 257–288.CrossRefPubMedGoogle Scholar
  6. 6.
    Bodor, N. (1977) Novel approaches for the design of membrane transport properties of drugs, in Design of Biopharmaceutical Properties through Prodrugs and Analogs (Roche, E. B., ed.), Academy of Pharmaceutical Sciences, Washington, DC, pp. 98–135.Google Scholar
  7. 7.
    Bodor, N. (1984) The soft drug approach. Chemtech 14, (1) 28–38.Google Scholar
  8. 8.
    Bodor, N. and Buchwald, P. (2000) Soft drug design: general principles and recent applications. Med. Res. Rev. 20, 58–101.CrossRefPubMedGoogle Scholar
  9. 9.
    Bodor, N., Kaminski, J. J., and Selk, S. (1980) Soft drugs. 1. Labile quaternary ammonium salts as soft antimicrobials. J. Med. Chem. 23, 469–474.CrossRefPubMedGoogle Scholar
  10. 10.
    Bodor, N. and Kaminski, J. J. (1980) Soft drugs. 2. Soft alkylating compounds as potential antitumor agents. J. Med. Chem. 23, 566–569.CrossRefPubMedGoogle Scholar
  11. 11.
    Bodor, N., Woods, R., Raper, C., Kearney, P., and Kaminski, J. (1980) Soft drugs. 3. A new class of anticholinergic agents. J. Med. Chem. 23, 474–480.CrossRefPubMedGoogle Scholar
  12. 12.
    Erhardt, P. W., Woo, C. M., Anderson, W. G., and Gorczynski, R. J. (1982) Ultrashort-acting β-adrenergic receptor blocking agents. 2. (Arlyoxy)propanolamines containing esters on the aryl function. J. Med. Chem. 25, 1408–1412.CrossRefPubMedGoogle Scholar
  13. 13.
    Erhardt, P. W. (1999) A prodrug and a soft drug., in Drug Metabolism. Databases and High Throughput Testing During Drug Design and Development (Erhardt, P. W., ed.), Blackwell Science, Oxford, pp. 62–69.Google Scholar
  14. 14.
    Feldman, P. L., James, M. K., Brackeen, M. F., Bilotta, J. M., Schuster, S. V., Lahey, A. P., et al. (1991) Design, synthesis, and pharmacological evaluation of ultrashort-to long-acting opioid analgetics. J. Med. Chem. 34, 2202–2208.CrossRefPubMedGoogle Scholar
  15. 15.
    Egan, T. D., Lemmens, H. J. M., Fiset, P., Hermann, D. J., Muir, K. T., Stanski, D. R., and Shafer, S. L. (1993) The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 79, 881–892.CrossRefPubMedGoogle Scholar
  16. 16.
    Bodor, N. (1981) Soft steroids having antiinflammatory activity, Belgian patent, BE889,563 (Cl. CO7J).Google Scholar
  17. 17.
    Druzgala, P., Hochhaus, G., and Bodor, N. (1991) Soft drugs. 10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate. J. Steroid Biochem. 38, 149–154.CrossRefGoogle Scholar
  18. 18.
    Noble, S. and Goa, K. L. (1998) Loteprednol etabonate. Clinical potential in the management of ocular inflammation. BioDrugs 10, 329–339.CrossRefPubMedGoogle Scholar
  19. 19.
    Hamilton, T. C. and Chapman, V. (1978) Intrinsic sympathomimetic activity of β-adrenoceptor blocking drugs at cardiac and vascular β-adrenoceptors. Life Sci. 23, 813–820.CrossRefPubMedGoogle Scholar
  20. 20.
    Machin, P. J., Hurst, D. N., and Osbond, J. M. (1985) β-Adrenoceptor activity of the stereoisomers of the bufuralol alcohol and ketone metabolites. J. Med. Chem. 28, 1648–1651.CrossRefPubMedGoogle Scholar
  21. 21.
    Francis, R. J., East, P. B., McLaren, S. J., and Larman, J. (1976) Determination of bufuralol and its metabolites in plasma by mass fragmentography and by gas chromatography with electron capture detection. Biomed. Mass. Spectrom. 3, 281–285.CrossRefPubMedGoogle Scholar
  22. 22.
    Hwang, S.-K., Juhasz, A., Yoon, S.-H., and Bodor, N. (2000) Soft drugs 22. Design, synthesis, and evaluation of soft bufuralol analogues. J. Med. Chem. 43, 1525–1532.CrossRefPubMedGoogle Scholar
  23. 23.
    Hassall, K. A. (1990) The Biochemistry and Uses of Pesticides. 2nd ed. Macmillan, London.Google Scholar
  24. 24.
    Hodgson, E. and Kuhr, R. J. (eds.) (1990) Safer Insecticides. Development and Use. Marcel Dekker, New York.Google Scholar
  25. 25.
    Bodor, N., Buchwald, P., and Huang, M.-J. (1999) The role of computational techniques in retrometabolic drug design strategies, in Computational Molecular Biology (Leszczynski, J., ed.), Elsevier, Amsterdam, Vol. 8 of series: Theoretical and Computational Chemistry, pp. 569–618.Google Scholar
  26. 26.
    Buchwald, P. and Bodor, N. (1999) Quantitative structure-metabolism relationships: steric and nonsteric effects in the enzymatic hydrolysis of noncongener carboxylic esters. J. Med. Chem. 42, 5160–5168.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Nicholas Bodor
    • 1
  • Peter Buchwald
    • 1
  1. 1.Department of Pharmaceutics, Center for Drug DiscoveryUniversity of Florida, College of PharmacyGainesville

Personalised recommendations