简介
Traditionally, incorporating optimal drug-like properties into a structural lead was not considered by medicinal chemists to be their responsibility. Instead, medicinal chemists felt that the undesirable drug-like properties in their drug candidates would be fixed by preclinical development scientists. However, that view has changed in the past 5a?10 years, resulting in another significant paradigm shift in drug discovery. The most significant aspect of this latest paradigm shift is the recognition by medicinal chemists that the drug-like properties of structural hits, structural leads, and drug candidates are intrinsic properties of the molecules and that it is the responsibility of the medicinal chemist to optimize not only the pharmacological properties but also the drug-like properties of these molecules. Therefore, assessment of these drug-like properties is now done early in the drug discovery process on structural hits and structural leads as well as the design of screening libraries. Optimization of these drug-like properties is done through an iterative process in close collaboration with preclinical development scientists. This process is analogous to the process used by the medicinal chemist to characterize and optimize the pharmacological activity of their structural hits, leads and drug candidates. Recognizing these changes in the paradigm by which drugs are discovered, the American Association of Pharmaceutical Scientists (AAPS) has recently organized and sponsored two focused workshops in the area of profiling drug-like properties during drug discovery. The first workshop, entitled "Pharmaceutical Profiling in Drug Discovery for Lead Selection", took place in Whippany, NJ on May 19-21, 2003. This workshop, which was co-sponsored by the American Chemical Society-Medicinal Chemistry Division and the Society for Biomolecular Screening, was focused on prediction, measurement, and utilization of drug-like properties during lead selection. From this workshop arose the book entitled Pharmaceutical Profiling in Drug discovery for Lead Selection, which was edited by Ronald T. Borchardt, Edward H. Kerns, Christopher A. Lipinski, Dhiren R. Thakker and Binghe Wang and published by AAPS Press (Arlington, VA) in 2004. The second workshop entitled "Optimizing the Drug-Like Properties of Leads in Drug Discovery" took place in Parsippany, NJ on September 19-22, 2004. This workshop, which was co-sponsored by the American Chemical Society-Medicinal Chemistry Division, American Chemical Society-North Jersey Section, American Society for Clinical Pharmacology and Therapeutics, European Federation for Pharmaceutical Sciences, International Society for the study of Xenobiotics, and the Society of Toxicology, was focused on the optimization of the drug-like properties of leads in drug discovery. If the strategies and the methodologies presented at this workshop were to be adopted by pharmaceutical and biotechnology companies, it is the belief of the workshopa's organizers that more higher quality drug candidates would be advancing into preclinical and clinical development resulting in more efficacious and safer drugs.
目录
1. Strategic Use of Preclinical Pharmacokinetic Studies and In Vitro
Models in Optimizing ADME Properties of Lead Compounds
Dhiren R. Thakker....................... ................... ..... 1
2. Role of Mechanistic Transport Studies in Lead Optimization
Jerome Hochman, Qin Mei, AMasayo Yamazaki, Cnvune Tang,
Thomawynt Prneksaritanont, Mark Bock, Sookhee Ha and Jinnn Lin .....25
3. Metabolic Activation-Role in Toxicity and Idiosyncratic
Reactions
John S. Walsh........................... .... ..............49
4. 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, Cindy Xia, Himua Yang, Vinita Uttamsingh,
Chiuang Lit, Sandeepraj Pusalkar,J. Scott Daniels, Ron Huang,
Mark Qian, Jing-Tao Wu, Kym Cardoza, Suresh K. Balani,
and G erald M iw a ....................................................8 1
5. Solubility, Solubilization and Dissolution in Drug Delivery
During Lead Optimization
M ichael J. H agem an ............................................................................99
6. Lipid-based Systems, Drug Exposure and Lead Optimization
William N. Charman, Susan A. Charman
and ChristopherJ. H. Porter...... ...... ..... ............................. 131
7. Biopharmaceutics Modeling and the Role of Dose
and Formulation on Oral Exposure
Brian R. Rohrs, Ph.D........ ........... ....................151
8. Application of Physicochemical Data to Support Lead
Optimization by Discovery Teams
Li Di and Edward ILH. Kerns ........................................ 167
9. Computational Models Supporting Lead Optimization
in Drug Discovery
Philip S. Burton, Italo Poggesi, Massimiliano Germani
and Jay 7 Goodwin .................................... 195
10. Prodrug Strategies for Improving Drug-Like Properties
Valentino . Stella ................................. .........221
11. The Application of Multivariate Data Analysis to
Compound Property Optimization
John W. Ellingboe ......................................243
12. Case History: Toxicology Biomarker Development
Using Toxicogenomics
David E. Watson, Timothy P Ryan and James L. Stevens ...................255
13. Predicting Idiosyncratic Drug Reactions
Alastair Cribb ......................... ..........................271
14. Elementary Predictive Toxicology for Advanced Applications
Constantine Kreatsoulas, Stephen K. Durham, Laura L. Custer
and Greg M. Pearl...................... ............... ...............301
15. The Application of PK/PD Modeling and Simulations During
Lead Optimization
Stuart Friedrich, Evelyn Lobo, Karen Zimmerman,
Anthony Borel, and Carlos 0. Garner......................... .........323
16. Early Preclinical Evaluation of Brain Exposure in Support
of Hit Identification and Lead Optimization
7Thomas]. Raub, Barry S. Lutzke, Paula K. Andrus
Geri A. Sawada and Brian A. Staton ............... ..................355
17. Optimizing Biomarker Development for Clinical Studies
at the Lead Optimization Stage of Drug Development
Geoffrey S Ginsburg, Julie Lekstromn-Himes and William Trepicchio .......411
18. The Relevance of Transporters in Determining
Drug Disposition
Hartinut Glaeser and Richard B. Kim........................................423
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