DRUG-LIKE PROPERTIES: CONCEPTS, STRUCTURE DESIGN AND METHODS
from ADME to Toxicity Optimization To order this title, and for more information, click here
By Edward Kerns, Wyeth Research, NJ, USA Li Di
Description 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. Understanding ADME/Tox is critical for all drug researchers,
owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. If the
properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource
for scientists engaged in, or preparing for, the selection and optimization process.
The authors describe how properties affect in
vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view,
such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in
drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various
methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties.
Audience
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.
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
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