Holladay The Organic Chemistry of Drug Design and Drug Action

3. Auflage 2014
ISBN: 978-0-12-382031-0
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 536 Seiten

The Organic Chemistry of Drug Design and Drug Action, Third Edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that rationalize drug action, which allows reader to extrapolate those core principles and mechanisms to many related classes of drug molecules. This new edition includes updates to all chapters, including new examples and references. It reflects significant changes in the process of drug design over the last decade and preserves the successful approach of the previous editions while including significant changes in format and coverage. This text is designed for undergraduate and graduate students in chemistry studying medicinal chemistry or pharmaceutical chemistry; research chemists and biochemists working in pharmaceutical and biotechnology industries. - Updates to all chapters, including new examples and references - Chapter 1 (Introduction): Completely rewritten and expanded as an overview of topics discussed in detail throughout the book - Chapter 2 (Lead Discovery and Lead Modification): Sections on sources of compounds for screening including library collections, virtual screening, and computational methods, as well as hit-to-lead and scaffold hopping; expanded sections on sources of lead compounds, fragment-based lead discovery, and molecular graphics; and deemphasized solid-phase synthesis and combinatorial chemistry - Chapter 3 (Receptors): Drug-receptor interactions, cation-p and halogen bonding; atropisomers; case history of the insomnia drug suvorexant - Chapter 4 (Enzymes): Expanded sections on enzyme catalysis in drug discovery and enzyme synthesis - Chapter 5 (Enzyme Inhibition and Inactivation): New case histories: - for competitive inhibition, the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib and Abelson kinase inhibitor, imatinib - for transition state analogue inhibition, the purine nucleoside phosphorylase inhibitors, forodesine and DADMe-ImmH, as well as the mechanism of the multisubstrate analog inhibitor isoniazid - for slow, tight-binding inhibition, the dipeptidyl peptidase-4 inhibitor, saxagliptin - Chapter 7 (Drug Resistance and Drug Synergism): This new chapter includes topics taken from two chapters in the previous edition, with many new examples - Chapter 8 (Drug Metabolism): Discussions of toxicophores and reactive metabolites - Chapter 9 (Prodrugs and Drug Delivery Systems): Discussion of antibody-drug conjugates.

Autoren/Hrsg.

Holladay, Mark W.

Inhaltsverzeichnis

1;Front Cover;1
2;The Organic Chemistry of Drug Design and Drug Action;4
3;Copyright;5
4;Dedications;6
5;Contents;8
6;Preface to the First Edition;14
7;Preface to the Second Edition;16
8;Preface to the Third Edition;18
9;Chapter 1 - Introduction;20
9.1;1.1. OVERVIEW;20
9.2;1.2. DRUGS DISCOVERED WITHOUT RATIONAL DESIGN;21
9.3;1.3. OVERVIEW OF MODERN RATIONAL DRUG DESIGN;26
9.4;1.4. EPILOGUE;33
9.5;1.5. GENERAL REFERENCES;34
9.6;1.6. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);35
9.7;REFERENCES;35
10;Chapter 2 - Lead Discovery and Lead Modification;38
10.1;2.1. LEAD DISCOVERY;39
10.2;2.2. LEAD MODIFICATION;73
10.3;2.3. GENERAL REFERENCES;114
10.4;2.4. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);121
10.5;REFERENCES;125
11;Chapter 3 - Receptors;142
11.1;3.1. INTRODUCTION;142
11.2;3.2. DRUG–RECEPTOR INTERACTIONS;144
11.3;3.3. GENERAL REFERENCES;176
11.4;3.4. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);176
11.5;REFERENCES;178
12;Chapter 4 - Enzymes;184
12.1;4.1. ENZYMES AS CATALYSTS;184
12.2;4.2. MECHANISMS OF ENZYME CATALYSIS;188
12.3;4.3. COENZYME CATALYSIS;194
12.4;4.4. ENZYME CATALYSIS IN DRUG DISCOVERY;215
12.5;4.5. GENERAL REFERENCES;217
12.6;4.6. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);218
12.7;REFERENCES;221
13;Chapter 5 - Enzyme Inhibition and Inactivation;226
13.1;5.1. WHY INHIBIT AN ENZYME?;227
13.2;5.2. REVERSIBLE ENZYME INHIBITORS;229
13.3;5.3. IRREVERSIBLE ENZYME INHIBITORS;257
13.4;5.4. GENERAL REFERENCES;277
13.5;5.5. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);280
14;Chapter 6 - DNA-Interactive Agents;294
14.1;6.1. INTRODUCTION;294
14.2;6.2. DNA STRUCTURE AND PROPERTIES;296
14.3;6.3. CLASSES OF DRUGS THAT INTERACT WITH DNA;306
14.4;6.4. GENERAL REFERENCES;338
14.5;6.5. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);338
14.6;REFERENCES;339
15;Chapter 7 - Drug Resistance and Drug Synergism;352
15.1;7.1. DRUG RESISTANCE;352
15.2;7.2. DRUG SYNERGISM (DRUG COMBINATION);365
15.3;7.3. GENERAL REFERENCES;371
15.4;7.4. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);371
15.5;REFERENCES;371
16;Chapter 8 - Drug Metabolism;376
16.1;8.1. INTRODUCTION;376
16.2;8.2. SYNTHESIS OF RADIOACTIVE COMPOUNDS;378
16.3;8.3. ANALYTICAL METHODS IN DRUG METABOLISM;380
16.4;8.4. PATHWAYS FOR DRUG DEACTIVATION AND ELIMINATION;382
16.5;8.5. GENERAL REFERENCES;426
16.6;8.6. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);427
17;Chapter 9 - Prodrugs and Drug Delivery Systems;442
17.1;9.1. ENZYME ACTIVATION OF DRUGS;442
17.2;9.2. MECHANISMS OF DRUG INACTIVATION;444
17.3;9.3. GENERAL REFERENCES;478
17.4;9.4. PROBLEMS (ANSWERS CAN BE FOUND IN THE APPENDIX AT THE END OF THE BOOK);478
17.5;REFERENCES;480
18;Appendix - Answers to Chapter Problems;488
18.1;CHAPTER 1;488
18.2;CHAPTER 2;488
18.3;CHAPTER 3;495
18.4;CHAPTER 4;498
18.5;CHAPTER 5;506
18.6;CHAPTER 6;511
18.7;CHAPTER 7;514
18.8;CHAPTER 8;514
18.9;CHAPTER 9;520
19;Index;526

Leseproben

Chapter 2 Lead Discovery and Lead Modification
Abstract
Chapter 2 focuses, in detail, on the many considerations encountered in lead discovery and lead modification stages of modern rational drug design, as typically practiced in pharmaceutical companies and many academic research laboratories. Examples emphasize how the concepts of organic chemistry are applied during the practice of these key stages of drug discovery. Major topics of discussion are the various sources for lead compounds, including virtual screening, computational methods, and fragment-based approaches, and desired properties of lead compounds. This is followed by an exploration of the objectives, considerations, and methods for subsequently optimizing lead compounds across multiple parameters such as potency, selectivity, and ADME properties. Approaches for the identification of the pharmacophore and for the determination of structure-activity relationships, including quantitative and other computational and molecular graphics-based methods, are discussed, and properties important to oral bioavailability and membrane permeability are described. Keywords
lead identificationendogenous ligandhigh throughput screeninghigh throughput organic synthesisdrug-like propertieslead-like propertiesvirtual screeningstructure-activity relationshipsbioisostereconformational constraintslipophilicitylog Pmembrane permeabilityoral bioavailabilityblood-brain barrierADMEpharmacokinetics Chapter Outline 2.1. Lead Discovery?20 2.1.1. General Considerations?20 2.1.2. Sources of Lead Compounds?20 2.1.2.1. Endogenous Ligands?20 2.1.2.2. Other Known Ligands?23 2.1.2.3. Screening of Compounds?24        2.1.2.3.1. Sources of Compounds for Screening?26            2.1.2.3.1.1. Natural Products?26            2.1.2.3.1.2 Medicinal Chemistry Collections and Other “Handcrafted” Compounds?27            2.1.2.3.1.3 High-Throughput Organic Synthesis?27        2.1.2.3.2. Drug-Like, Lead-Like, and Other Desirable Properties of Compounds for Screening?32        2.1.2.3.3. Random Screening?36        2.1.2.3.4. Targeted (or Focused) Screening, Virtual Screening, and Computational Methods in Lead Discovery?36        2.1.2.3.5. Hit-To-Lead Process?43        2.1.2.3.6. Fragment-based Lead Discovery?45 2.2. Lead Modification?54 2.2.1. Identification of the Active Part: The Pharmacophore?55 2.2.2. Functional Group Modification?57 2.2.3. Structure–Activity Relationships?57 2.2.4. Structure Modifications to Increase Potency, Therapeutic Index, and ADME Properties?59 2.2.4.1. Homologation?60 2.2.4.2. Chain Branching?61 2.2.4.3. Bioisosterism?62 2.2.4.4. Conformational Constraints and Ring-Chain Transformations?66 2.2.4.5. Peptidomimetics?68 2.2.5. Structure Modifications to Increase Oral Bioavailability and Membrane Permeability?72 2.2.5.1. Electronic Effects: The Hammett Equation?72 2.2.5.2. Lipophilicity Effects?74        2.2.5.2.1. Importance of Lipophilicity?74        2.2.5.2.2. Measurement of Lipophilicities?74        2.2.5.2.3. Computer Automation of logP Determination?78        2.2.5.2.4. Membrane Lipophilicity?79 2.2.5.3. Balancing Potency of Ionizable Compounds with Lipophilicity and Oral Bioavailability?79 2.2.5.4. Properties that Influence Ability to Cross the Blood–Brain Barrier?81 2.2.5.5. Correlation of Lipophilicity with Promiscuity and Toxicity?82 2.2.6. Computational Methods in Lead Modification?83 2.2.6.1. Overview?83 2.2.6.2. Quantitative Structure–Activity Relationships (QSARs)?83        2.2.6.2.1. Historical Overview. Steric Effects: The Taft Equation and Other Equations?83        2.2.6.2.2. Methods Used to Correlate Physicochemical Parameters with Biological Activity?84            2.2.6.2.2.1 Hansch Analysis: A Linear Multiple Regression Analysis?84            2.2.6.2.2.2 Manual Stepwise Methods: Topliss Operational Schemes and Others?85            2.2.6.2.2.3 Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others?87            2.2.6.2.2.4 Free and Wilson or de Novo Method?88            2.2.6.2.2.5 Computational Methods for ADME Descriptors?89 2.2.6.3. Scaffold Hopping?89 2.2.6.4. Molecular Graphics-Based Lead Modification?90 2.2.7. Epilogue?93 2.3. General References?95 2.4. Problems?102 References?106 Lead Discovery
General Considerations
As discussed in the drug discovery overview in Chapter 1, identification of suitable lead compounds provides starting points for lead optimization, during which leads are modified to achieve requisite potency and selectivity, as well as absorption, distribution, metabolism, and excretion (ADME), and intellectual property (patent) position. Given the hurdles often presented by these multiple and diverse objectives, identification of the best lead compounds can be a critical factor to the overall success of a drug discovery program. The approach to lead identification taken in a given drug discovery program will usually take into account any known ligand (a smaller molecule that binds to a receptor) for the target. At one extreme, if there are already marketed drugs for a particular target, these may serve as lead compounds; however, in this case, establishing a suitable intellectual property position may be the greatest challenge. On the other hand, whereas the endogenous ligand (the molecule that binds to a biological target in an organism and is believed to be responsible for the native activity of the target) has provided good lead structures for many programs, the endogenous ligand for a new biological target may not be well characterized, or the only known ligand may not be attractive as a lead compound. For example, if an endogenous ligand is a complex molecule that is not readily amenable to synthetic modification or has some other undesirable properties that are not reasonably addressable, it may not be attractive as a lead, and other approaches to lead discovery must be considered. In the next few sections, we will first provide additional examples of endogenous or other known ligands as lead compounds to complement the examples given in Chapter 1, and then we will turn to a more detailed discussion of alternative approaches to lead discovery. Sources of Lead Compounds
Lead compounds can be acquired from a variety of sources: endogenous ligands, e.g., substrates for enzymes and transporters or agonists for receptors; other known ligands, including marketed drugs, compounds isolated in drug metabolism studies, and compounds used in clinical trials; and through screening of compounds, including natural products and other chemical libraries, either at random or in a targeted approach. Endogenous Ligands Rational approaches are important routes to lead discovery. The first step is to identify the cause for the disease state. Many diseases, or at least the symptoms of diseases, arise from an imbalance (either excess or deficiency) of a particular chemical in the body, from the invasion of a foreign organism, or from aberrant cell growth. As will be discussed in later chapters, the effects of the imbalance can be corrected by antagonism or agonism of a receptor (see Chapter 3) or by inhibition of a particular enzyme (see Chapter 5); interference with deoxyribonucleic acid (DNA) biosynthesis or function (see Chapter 6) is another important approach to treating diseases arising from microorganisms or aberrant cell growth. Once the relevant biochemical system is identified, initial lead compounds become the endogenous receptor ligands or enzyme substrates. In Chapter 1, the example of dopamine as a lead compound for the...