Optimizing the "Drug-Like" Properties of Leads in Drug Discovery

1. Front Matter

   Pages i-x

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2. Strategic Use of Preclinical Pharmacokinetic Studies and In Vitro Models in Optimizing ADME Properties of Lead Compounds

   • Dhiren R. Thakker

   Pages 1-23

3. Role of Mechanistic Transport Studies in Lead Optimization

   • Jerome Hochman, Qin Mei, Masayo Yamazaki, Cuyue Tang, Thomayant Prueksaritanont, Mark Bock et al.

   Pages 25-47

4. Metabolic Activation-Role in Toxicity and Idiosyncratic Reactions

   • John S. Walsh

   Pages 49-80

5. Case History — Use of ADME Studies for Optimization of Drug Candidates

   • Liang-Shang Gan, Frank W. Lee, Nelamangala Nagaraja, Ping Li, Jason Labutti, Wei Yin et al.

   Pages 81-97

6. Solubility, Solubilization and Dissolution in Drug Delivery During Lead Optimization

   • Michael J. Hageman

   Pages 99-130

7. Lipid-based Systems, Drug Exposure and Lead Optimization

   • William N. Charman, Susan A. Charman, Christopher J. H. Porter

   Pages 131-150

8. Biopharmaceutics Modeling and the Role of Dose and Formulation on Oral Exposure

   • Brian R. Rohrs

   Pages 151-166

9. Application of Physicochemical Data to Support Lead Optimization by Discovery Teams

   • Li Di, Edward H. Kerns

   Pages 167-193

10. Computational Models Supporting Lead Optimization in Drug Discovery

    • Philip S. Burton, Italo Poggesi, Massimiliano Germani, Jay T. Goodwin

    Pages 195-219

11. Prodrug Strategies for Improving Drug-Like Properties

    • Valentino J. Stella

    Pages 221-242

12. The Application of Multivariate Data Analysis to Compound Property Optimization

    • John W. Ellingboe

    Pages 243-254

13. Case History: Toxicology Biomarker Development Using Toxicogenomics

    • David E. Watson, Timothy P. Ryan, James L. Stevens

    Pages 255-270

14. Predicting Idiosyncratic Drug Reactions

    • Alastair Cribb

    Pages 271-299

15. Elementary Predictive Toxicology for Advanced Applications

    • Constantine Kreatsoulas, Stephen K. Durham, Laura L. Custer, Greg M. Pearl

    Pages 301-322

16. The Application of PK/PD Modeling and Simulations During Lead Optimization

    • Stuart Friedrich, Evelyn Lobo, Karen Zimmerman, Anthony Borel, Carlos O. Garner

    Pages 323-353

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

    • Thomas J. Raub, Barry S. Lutzke, Paula K. Andrus, Geri A. Sawada, Brian A. Staton

    Pages 355-410

18. Optimizing Biomarker Development for Clinical Studies at the Lead Optimization Stage of Drug Development

    • Geoffrey S Ginsburg, Julie Lekstrom-Himes, William Trepicchio

    Pages 411-421

19. The Relevance of Transporters in Determining Drug Disposition

    • Hartmut Glaeser, Richard B. Kim

    Pages 423-459

20. Back Matter

    Pages 461-511

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Drug discovery and development is a very complex, costly, and ti- consuming process. Because of the uncertainties associated with predicting the pharmacological effects and the toxicity characteristics of new chemical entities in man, their clinical development is quite prone to failure. In recent years, phar- ceutical companies have come under increasing pressure to introduce new blockbuster drugs into the marketplace more rapidly. Companies have responded to these pressures by introducing new technologies and new strategies to expedite drug discovery and development. Drug discovery and development have traditionally been divided into three separate processes (i. e. , discovery research, preclinical development, and clinical development) that ideally should be integrated both organizationally and functionally. Instead, separate and distinct discovery research, preclinical development, and clinical development divisions were created within many companies during the 1980s and 1990s, Because of their isolation, scientists in the discovery research divisions often were advancing drug candidates into preclinical development that had marginal drug-like properties. For the purpose of this presentation, “drug-like” properties refer to the molecule’s physicochemical, absorption-distribution-metabolism-excretion (ADME), and toxicological properties. Lacking optimal drug-like properties often caused these drug candidates to fail in preclinical or clinical development.

• Borchardt
• Discovery
• Drug
• Leads
• Like
• Optimizing
• Properties
• lead

• University of Kansas, Lawrence, USA

  Ronald T. Borchardt

• Wyeth Research, Monmouth Junction, USA

  Edward H. Kerns

• Pfizer, Inc., Kalamazoo, USA

  Michael J. Hageman

• University of North Carolina, Chapel Hill, USA

  Dhiren R. Thakker

• Eli Lilly Research Laboratory, Greenfield, USA

  James L. Stevens

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