Drug research is a fulfilling career, because new drugs can improve human health, quality of life, and life span. For scientists dedicated to drug research, it can also be a supremely challenging mission, owing to the numerous attributes that must be simultaneously optimized to arrive at an efficacious drug-like compound. ADME/Tox (absorption, distribution, metabolism, elimination, toxicity) is one of these challenges. Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, typically only a fraction of these have sufficient ADME/Tox properties to become a drug product. This book is devoted to providing you, the drug research scientist or student, with an introduction to ADME/Tox property concepts, structure design, and methodology to help you succeed with these challenges.
Chemists will be aided by the case studies, structure-property relationships, and structure modification strategies in this book. These assist in diagnosing the substructures of a lead structure that are not drug-like and suggest ideas for ADME/Tox structure design. Overviews of property methods provide the background needed to accurately interpret and apply the data for informed decisions. For ADME/Tox scientists, insights on property assays assist with selecting methods and generating data that impacts projects.
Biologists/pharmacologists will benefit from an increased understanding of ADME/Tox concepts. This is especially important, because in recent years the application of property data has expanded from optimizing in vivo pharmacokinetics and safety to biological assays. Low solubility, chemical instability, and low permeability can greatly affect bioassay data. Equipped with this understanding, biologists are better able to optimize bioassays and include property affects in data interpretation.
Accordingly, understanding ADME/Tox is important for all drug researchers, owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. ADME/Tox properties are a crucial aspect of clinical candidate quality. If the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. ADME/Tox has become integrated in the drug discovery process and is a tremendous asset in guiding selection and optimization of precious leads. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. The authors wish you success in creating the pharmaceuticals of the future that will benefit all people.
Key Features
- Serves as an essential working handbook aimed at scientists and students in medicinal chemistry.
- Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies.
- Discusses improvements in pharmacokinetics from a practical chemist's standpoint.
Contents
Preface
Introductory Concepts
- 1. Introduction
- 2. The Advantages of Good Drug-like Properties
- 3. Barriers to Drug Exposure in Living Systems
Physicochemical Properties
- 4. Rules for Rapid Property Profiling From Structure
- 5. Lipophilicity
- 6. pKa
- 7. Solubility
- 8. Permeability
Disposition, Metabolism and Safety
- 9. Transporters
- 10. Blood-Brain Barrier
- 11. Metabolic Stability
- 12. Plasma Stability
- 13. Solution Stability
- 14. Plasma Protein Binding
- 15. Cytochrome P450 Inhibition
- 16. hERG Blocking
- 17. Toxicity
- 18. Integrity and Purity
- 19. Pharmacokinetics
- 20. Lead-like Compounds
- 21. Strategies for Integrating Drug-Like Properties Into Drug Discovery
Methods
- 22. Methods for Profiling Drug-like Properties: General Concepts
- 23. Lipophilicity Methods
- 24. pKa Methods
- 25. Solubility Methods
- 26. Permeability Methods
- 27. Transporter Methods
- 28. Blood-Brain Barrier Methods
- 29. Metabolic Stability Methods
- 30. Plasma Stability Methods
- 31. Solution Stability Methods
- 32. CYP Inhibition Methods
- 33. Plasma Protein Binding Methods
- 34. hERG Methods
- 35. Toxicity Methods
- 36. Integrity and Purity Methods
- 37. Pharmacokinetics Methods
Specific Topics
- 38. Diagnosing and Improving Pharmacokinetic Performance
- 39. Prodrugs
- 40. Effects of Properties on Biological Assays
- 41. Formulation
Answers to Problems
Appendix I: General References
Appendix II: Glossary
Readership
Medicinal chemists in private industry, research centers and government labs; ADME scientists who develop assays and perform measurements, as well as instrument vendors and software companies in this area; and students in medicinal chemistry and pharmaceutical sciences.
Product Details
- Hardcover: 552 pages
- Publisher: Academic Press; 1 edition (February 19, 2008)
- Language: English
- ISBN-10: 0123695201
- ISBN-13: 978-0123695208
- Product Dimensions: 10.3 x 7.3 x 1.4 inches
List Price: $99.95