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Structural pairwise comparisons of HLM stability of phenyl derivatives: Introduction of the Pfizer metabolism index (PMI) and metabolism-lipophilicity efficiency (MLE)

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Abstract

Data mining by pairwise comparison of over 150,000 human liver microsome (HLM) intrinsic clearance values stored within the internal Pfizer database has been performed by an automated tool. Systematic probability tables of specific structural changes on the intrinsic clearance of phenyl derivatives have been generated. From these data two new parameters, the Pfizer Metabolism Index (PMI) and Metabolism-Lipophilicity Efficiency (MLE) are introduced for each fragment. The findings are applied to a Topliss style analysis that focuses on metabolic stability.

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Acknowledgements

We thank Kevin Beaumont, Alan Brown, Iain Gardner, David Hepworth and Rob Webster for helpful discussions.

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Authors and Affiliations

  1. Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer PGRD, Sandwich, Kent, CT13 9NJ, United Kingdom

    Mark L. Lewis & Lourdes Cucurull-Sanchez

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  1. Mark L. Lewis
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  2. Lourdes Cucurull-Sanchez
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Correspondence to Mark L. Lewis.

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Lewis, M.L., Cucurull-Sanchez, L. Structural pairwise comparisons of HLM stability of phenyl derivatives: Introduction of the Pfizer metabolism index (PMI) and metabolism-lipophilicity efficiency (MLE). J Comput Aided Mol Des 23, 97–103 (2009). https://doi.org/10.1007/s10822-008-9242-3

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  • DOI: https://doi.org/10.1007/s10822-008-9242-3

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