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Designing safer (soft) drugs by avoiding the formation of toxic and oxidative metabolites

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Abstract

Integration metabolic considerations into the drug-design process can allow safer pharmaceuticals to be designed. “Soft” drugs are designed to be deactivated in a predictable and controllable way after achieving their therapeutic role. They are designed to be metabolized rapidly and by avoiding oxidative pathways into inactive and nontoxic species. Successful application of such design principles has already resulted in a number of marketed drugs. The present article illustrates advantages inherent in avoiding the formation of oxidative metabolites, with examples that include soft bufuralol analogs and soft insecticides such as chlorobenzilate and malathion. Design principles for various soft drug classes are briefly summarized together with computerized tools intended to make the application of these principles more quantitative and more accessible.

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References

  1. Albert, A. (1985) Selective Toxicity. The Physico-Chemical Basis of Therapy. 7th ed. Chapman and Hall, London, p. 750.

    Google Scholar 

  2. 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. Durg Metab. Rev. 10, 59–87.

    CAS  Google Scholar 

  3. 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 

  4. 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, Inc., New York pp. 53–166.

    Google Scholar 

  5. Leinweber, F.-J. (1987) Possible physiological roles of carboxylic ester hydrolases. Drug Metab. Rev. 18, 379–439.

    PubMed  CAS  Google Scholar 

  6. Satoh, T. and Hosokawa, M. (1998) The mammalian carboxylesterases: from molecules to functions. Annu. Rev. Pharmacol. Toxicol. 38, 257–288.

    Article  PubMed  CAS  Google Scholar 

  7. 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, D.C. pp. 98–135.

    Google Scholar 

  8. Bodor, N. (1984) The soft drug approach. Chemtech 14(1), 28–38.

    CAS  Google Scholar 

  9. Bodor, N. and Buchwald, P. (2000) Soft drug design: general principles and recent applications. Med. Res. Rev. 20, 58–101.

    Article  PubMed  CAS  Google Scholar 

  10. Bodor, N. and Buchwald, P. (2003) Retrometabolism-based drug design and targeting. In: Burger’s Medicinal Chemistry, 6th ed. (Abraham, D., ed.), Wiley, New York, pp. 553–608.

    Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. Bodor, N. and Kaminski, J. J. (1980) Soft drugs. 2. Soft alkylating compounds as potential antitumor agents. J. Med. Chem. 23, 566–569.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. Erhardt, P. W., Woo, C. M., Anderson, W. G. and Gorczynski, R. J. (1982) Ultra-short-acting β-adrenergic receptor blocking agents. 2. (Arlyoxy)propanolamines containing esters on the aryl function. J. Med. Chem. 25, 1408–1412.

    Article  PubMed  CAS  Google Scholar 

  15. Erhardt, P. W. (1999) A prodrug and a soft drug. In: Drug Metabolism. Databases and High Throughput Testing During Drug Design and Developmen (Erhardt, P. W., ed.), Blackwell Science, Oxford pp. 62–69.

    Google Scholar 

  16. Feldman, P. L., James, M. K., Brackeen, M. F., et al. (1991) Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics. J. Med. Chem. 34, 2202–2208.

    Article  PubMed  CAS  Google Scholar 

  17. Egan, T. D., Lemmens, H. J. M., Fiset, P., et al. (1993) The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 79, 881–892.

    Article  PubMed  CAS  Google Scholar 

  18. Bodor, N. (1981) Soft steroids having antiinflammatory activity. Belgian Patent, BE889,563 (Cl. CO7J), Bruxelles, Belgium.

    Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. Noble, S. and Goa, K. L. (1998) Loteprednol etabonate. Clinical potential in the management of ocular inflammation. BioDrugs 10, 329–339.

    Article  CAS  Google Scholar 

  21. Bodor, N. and Buchwald, P. (2002) Design and development of a soft corticosteroid, loteprednol etabonate. In: Inhaled Steroids in Asthma. Optimizing Effects in the Airways (Schleimer, R. P., O’Byrne, P. M., Szefler, S. J., and Brattsand, R., eds.) Marcel Dekker, New York, Lung Biology in Health and Disease, vol. 163, Vol. pp. 541–564.

    Google Scholar 

  22. Hamilton, T. C. and Chapman, V. (1978) Intrinsic sympathomimetic activity of b-adrenoceptor blocking drugs at cardiac and vascular b-adrenoceptors. Life Sci. 23, 813–820.

    Article  PubMed  CAS  Google Scholar 

  23. Machin, P. J., Hurst, D. N., and Osbond, J. M. (1985) b-Adrenoceptor activity of the stereoisomers of the bufuralol alcohol and ketone metabolites. J. Med. Chem. 28, 1648–1651.

    Article  PubMed  CAS  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. Dayer, P., Leemann, T., Kupfer, A., Kronbach, T., and Meyer, U. A. (1986) Stereo- and regioselectivity of hepatic oxidation in man-effect of the debrisoquine/sparteine phenotype on bufuralol hydroxylation. Eur. J. Clin. Pharmacol. 31, 313–318.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. Hassall, K. A. (1990) The Biochemistry and Uses of Pesticides, 2nd ed. Macmillan, London, p. 536.

    Google Scholar 

  28. Hodgson, E. and Kuhr, R. J. (1990) Safer Insecticides. Development and Use. Marcel Dekker, New York, p. 593.

    Google Scholar 

  29. 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, Theoretical and Computational Chemistry, Vol. 8, Vol. pp. 569–618.

    Google Scholar 

  30. Buchwald, P. and Bodor, N. (2002) Computer-aided drug design: the role of quantitative structure-property, structure-activity, and structure-metabolism relationships (QSPR, QSAR, QSMR). Drugs Future 27, 577–588.

    Article  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. Buchwald, P. (2001) Structure-metabolism relationships: steric effects and the enzymatic hydrolysis of carboxylic esters. Min. Rev. Med. Chem. 1, 101–111.

    Article  CAS  Google Scholar 

  33. Buchwald, P. and Bodor, N. (2000) Structure-based estimation of enzymatic hydrolysis rates and its application in computer-aided retrometabolic drug design. Pharmazie 55, 210–217.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. IVAX Research Inc., 4400 Biscayne Boulecard, 33137, Miami, FL

    Nicholas Bodor & Peter Buchwald

  2. Center for Drug Discovery, University of Florida, 32610, Gainesville, FL

    Nicholas Bodor

Authors
  1. Nicholas Bodor
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  2. Peter Buchwald
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Correspondence to Nicholas Bodor.

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Bodor, N., Buchwald, P. Designing safer (soft) drugs by avoiding the formation of toxic and oxidative metabolites. Mol Biotechnol 26, 123–132 (2004). https://doi.org/10.1385/MB:26:2:123

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