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Tactics to Avoid Inhibition of Cytochrome P450s

Part of the Topics in Medicinal Chemistry book series (TMC,volume 9)

Abstract

This chapter will focus on avoiding inhibition of cytochrome P450s. This problem leads to drug–drug interactions that can severely restrict the patients who can receive a particular drug. The first sections [(1) background and motivation, (2) the structure of the cytochrome P450s, and (3) overview of the mechanism of cytochrome P450s] provide essential background to understanding both the problem and some of the solutions. The subsequent three sections [(4) trends for inhibition to be modulated by bulk properties (database analysis), (5) metal chelation, and (6) reactive metabolites and mechanism-based inhibition] will outline some general methods for tackling the problem, and each section has a summary in which the strategic approaches that follow from the information are presented. In the final section [(7) examples of successful reduction of P450 liability], how these strategies can be reduced to tactical application is illustrated with published examples.

Keywords

  • Cytochrome P450
  • Inhibition
  • Lead optimization
  • Medicinal chemistry

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Notes

  1. 1.

    Data that are categorized as either IC50, AC50 or potency and have molar units have been included. Properties are calculated on all compounds with molecular weight <1,000 Da.

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Acknowledgments

I am grateful for the support of my former employers AstraZeneca in the preparation of this manuscript and for providing hands-on experience of tackling the inhibition of cytochrome P450s. Anne Hersey of the EBI is thanked for assistance in obtaining and processing the Chembl dataset.

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Correspondence to Andrew G. Leach .

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Leach, A.G. (2013). Tactics to Avoid Inhibition of Cytochrome P450s. In: Meanwell, N. (eds) Tactics in Contemporary Drug Design. Topics in Medicinal Chemistry, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_25

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