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Early Preclinical Evaluation of Brain Exposure in Support of Hit Identification and Lead Optimization

  • Chapter
Optimizing the “Drug-Like” Properties of Leads in Drug Discovery

Part of the book series: Biotechnology: Pharmaceutical Aspects ((PHARMASP,volume IV))

Abstract

Assessing brain exposure continues to be a central theme for multiple therapeutic areas within the pharmaceutical industry. In addition to optimizing delivery to CNS targets, brain exposure is considered for unwanted CNS access for either on-target activity or for off-target CNS toxicity or adverse events. The biopharmaceutical scientist is challenged to arrive at a rational strategy that is functional within the constraints of limited resources. Common strategies are integrated combinations of in silico, in vitro, and in vivo methods (Caldwell et al., 2001). The appropriate strategy used depends upon the need, i.e., to drive chemistry or to establish a pharmacokinetic-pharmacodynamic relationship. We believe that a rigorous strategy is best so that the best lead series are selected. The intent is to anticipate liabilities of a lead series such that subsequent lead optimization cycle time and clinical attrition rates are ultimately reduced. The rigorous methods should deliver value by aiding synthetic chemistry direction while filtering out difficult templates. We also advocate the use of animal models as early as possible to establish a realistic perspective around the plethora of higher-throughput screening assay data. This application obviously challenges one to increase the capacity of these in vivo assays without compromising data quality or wasting vital and limited people resources.

Retired from Pharmacia Corp., Kalamazoo, MI

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Authors and Affiliations

  1. Drug Disposition Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285

    Thomas J. Raub, Barry S. Lutzke, Geri A. Sawada & Brian A. Staton

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  1. Thomas J. Raub
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  2. Barry S. Lutzke
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  3. Paula K. Andrus
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  4. Geri A. Sawada
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Editor information

Editors and Affiliations

  1. University of Kansas, Lawrence, KS, 66045, USA

    Ronald T. Borchardt

  2. Wyeth Research, Monmouth Junction, NJ, 08852, USA

    Edward H. Kerns

  3. Pfizer, Inc., Kalamazoo, MI, 49007, USA

    Michael J. Hageman

  4. University of North Carolina, Chapel Hill, NC, 27599, USA

    Dhiren R. Thakker

  5. Eli Lilly Research Laboratory, Greenfield, IN, 46285, USA

    James L. Stevens

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Raub, T.J., Lutzke, B.S., Andrus, P.K., Sawada, G.A., Staton, B.A. (2006). Early Preclinical Evaluation of Brain Exposure in Support of Hit Identification and Lead Optimization. In: Borchardt, R.T., Kerns, E.H., Hageman, M.J., Thakker, D.R., Stevens, J.L. (eds) Optimizing the “Drug-Like” Properties of Leads in Drug Discovery. Biotechnology: Pharmaceutical Aspects, vol IV. Springer, New York, NY. https://doi.org/10.1007/978-0-387-44961-6_16

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