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The Organic Chemistry of Drug Design and Drug Action
 
 

The Organic Chemistry of Drug Design and Drug Action, 3rd Edition

 
The Organic Chemistry of Drug Design and Drug Action, 3rd Edition,Richard B. Silverman,Mark W. Holladay,ISBN9780123820303
 
 
 

  &      

Academic Press

9780123820303

9780123820310

536

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 the reader to extrapolate those core principles and mechanisms to many related classes of drug molecules.

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Key Features

New to this edition:

  • 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

Description

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 the reader to extrapolate those core principles and mechanisms to many related classes of drug molecules. This new edition reflects significant changes in the process of drug design over the last decade. It preserves the successful approach of the previous editions while including significant changes in format and coverage.

Readership

Undergraduate and graduate students in chemistry studying medicinal chemistry or pharmaceutical chemistry; research chemists and biochemists working in pharmaceutical and biotechnology industries.

Richard B. Silverman

Ph.D Organic Chemistry

Professor Richard B. Silverman received his B.S. degree in chemistry from The Pennsylvania State University in 1968 and his Ph.D. degree in organic chemistry from Harvard University in 1974 (with time off for a two-year military obligation from 1969-1971). After two years as a NIH postdoctoral fellow in the laboratory of the late Professor Robert Abeles in the Graduate Department of Biochemistry at Brandeis University, he joined the chemistry faculty at Northwestern University. In 1986, he became Professor of Chemistry and Professor of Biochemistry, Molecular Biology, and Cell Biology. In 2001, he became the Charles Deering McCormick Professor of Teaching Excellence for three years, and since 2004 he has been the John Evans Professor of Chemistry. His research can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents acting on enzymes and receptors. His awards include DuPont Young Faculty Fellow (1976), Alfred P. Sloan Research Fellow (1981-1985), NIH Research Career Development Award (1982-1987), Fellow of the American Institute of Chemists (1985), Fellow of the American Association for the Advancement of Science (1990), Arthur C. Cope Senior Scholar Award of the American Chemical Society (2003), Alumni Fellow Award from Pennsylvania State University (2008), Medicinal Chemistry Hall of Fame of the American Chemical Society (2009), the Perkin Medal from the Society of Chemical Industry (2009), the Hall of Fame of Central High School of Philadelphia (2011), the E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances from the American Chemical Society (2011), Fellow of the American Chemical Society (2011), Sato Memorial International Award of the Pharmaceutical Society of Japan (2012), Roland T. Lakey Award of Wayne State University (2013), BMS-Edward E. Smissman Award of the American Chemical Society (2013), the Centenary Prize of the Royal Society of Chemistry (2013), and the Excellence in Medicinal Chemistry Prize of the Israel Chemical Society (2014). Professor Silverman has published over 320 research and review articles, holds 49 domestic and foreign patents, and has written four books (The Organic Chemistry of Drug Design and Drug Action is translated into German and Chinese). He is the inventor of LyricaTM, a drug marketed by Pfizer for epilepsy, neuropathic pain, fibromyalgia, and spinal cord injury pain; currently, he has another CNS drug in clinical trials.

Affiliations and Expertise

Northwestern University, Evanston, IL, USA

View additional works by Richard B. Silverman

Mark W. Holladay

Dr. Mark W. Holladay is Vice President of Drug Discovery and Medicinal Chemistry at Ambit Biosciences (San Diego, California) where he leads drug discovery programs in oncology and autoimmune diseases and has contributed to compounds in clinical development. He began his drug hunting career at Abbott Laboratories where he achieved the position of Volwiler Associate Research Fellow as a medicinal chemist and project leader in the Neurosciences Research Area. He also conducted collaborative drug discovery research as a member of contract research organizations including Biofocus and Discovery Partners International. He is a co-author on over 70 peer-reviewed research articles, reviews, or chapters and is named as an inventor on over 40 patents and patent applications. Dr. Holladay earned his undergraduate degree from Vanderbilt University, his Ph.D. at Northwestern University under the direction of Professor Richard B. Silverman, and conducted postdoctoral studies with Professor Daniel H. Rich at the University of Wisconsin-Madison.

Affiliations and Expertise

Ambit Biosciences, San Diego, CA, USA

The Organic Chemistry of Drug Design and Drug Action, 3rd Edition

1. Introduction
1.1. Overview
1.2. Drugs Discovered without Rational Design
     1.2.1. Medicinal Chemistry Folklore
     1.2.2. Discovery of Penicillins
     1.2.3. Discovery of Librium
     1.2.4. Discovery of Drugs through Metabolism Studies
     1.2.5. Discovery of Drugs through Clinical Observations
1.3. Overview of Modern Rational Drug Design
     1.3.1. Overview of Drug Targets
     1.3.2. Identification and Validation of Targets for Drug Discovery
     1.3.3. Alternatives to Target-Based Drug Discovery
     1.3.4. Lead Discovery
     1.3.5. Lead Modification (Lead Optimization)
          1.3.5.1. Potency
          1.3.5.2. Selectivity
          1.3.5.3. Absorption, Distribution, Metabolism, and Excretion (ADME)
          1.3.5.4. Intellectual Property Position
     1.3.6. Drug Development
          1.3.6.1. Preclinical Development
          1.3.6.2. Clinical Development (Human Clinical Trials)
          1.3.6.3. Regulatory Approval to Market the Drug
1.4. Epilogue
1.5. General References
1.6. Problems
References
2. Lead Discovery and Lead Modification
2.1. Lead Discovery
     2.1.1. General Considerations
     2.1.2. Sources of Lead Compounds
          2.1.2.1. Endogenous Ligands
          2.1.2.2. Other Known Ligands
          2.1.2.3. Screening of Compounds
               2.1.2.3.1. Sources of Compounds for Screening
                    2.1.2.3.1.1. Natural Products
                    2.1.2.3.1.2. Medicinal Chemistry Collections and Other "Handcrafted" Compounds
                    2.1.2.3.1.3. High-Throughput Organic Synthesis
                         2.1.2.3.1.3.1. Solid-Phase Library Synthesis
                         2.1.2.3.1.3.2. Solution-Phase Library Synthesis
                         2.1.2.3.1.3.3. Evolution of HTOS
               2.1.2.3.2. Drug-Like, Lead-Like, and Other Desirable Properties of Compounds for Screening
               2.1.2.3.3. Random Screening
               2.1.2.3.4. Targeted (or Focused) Screening, Virtual Screening, and Computational Methods in Lead Discovery
                    2.1.2.3.4.1. Virtual Screening Database
                    2.1.2.3.4.2. Virtual Screening Hypothesis
               2.1.2.3.5. Hit-To-Lead Process
               2.1.2.3.6. Fragment-based Lead Discovery
2.2. Lead Modification
     2.2.1. Identification of the Active Part: The Pharmacophore
     2.2.2. Functional Group Modification
     2.2.3. Structure-Activity Relationships
     2.2.4. Structure Modifications to Increase Potency, Therapeutic Index, and ADME Properties
          2.2.4.1. Homologation
          2.2.4.2. Chain Branching
          2.2.4.3. Bioisosterism
          2.2.4.4. Conformational Constraints and Ring-Chain Transformations
          2.2.4.5. Peptidomimetics
     2.2.5. Structure Modifications to Increase Oral Bioavailability and Membrane Permeability
          2.2.5.1. Electronic Effects: The Hammett Equation
          2.2.5.2. Lipophilicity Effects
               2.2.5.2.1. Importance of Lipophilicity
               2.2.5.2.2. Measurement of Lipophilicities
               2.2.5.2.3. Computer Automation of log P Determination
               2.2.5.2.4. Membrane Lipophilicity
          2.2.5.3. Balancing Potency of Ionizable Compounds with Lipophilicity and Oral Bioavailability
          2.2.5.4. Properties that Influence Ability to Cross the Blood-Brain Barrier
          2.2.5.5. Correlation of Lipophilicity with Promiscuity and Toxicity
     2.2.6. Computational Methods in Lead Modification
          2.2.6.1. Overview
          2.2.6.2. Quantitative Structure-Activity Relationships (QSARs)
               2.2.6.2.1. Historical Overview. Steric Effects: The Taft Equation and Other Equations
               2.2.6.2.2. Methods Used to Correlate Physicochemical Parameters with Biological Activity
                    2.2.6.2.2.1. Hansch Analysis: A Linear Multiple Regression Analysis
                    2.2.6.2.2.2. Manual Stepwise Methods: Topliss Operational Schemes and Others
                    2.2.6.2.2.3. Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others
                    2.2.6.2.2.4. Free and Wilson or de Novo Method
                    2.2.6.2.2.5. Computational Methods for ADME Descriptors
          2.2.6.3. Scaffold Hopping
          2.2.6.4. Molecular Graphics-Based Lead Modification
     2.2.7. Epilogue
2.3. General References
2.4. Problems
References
3. Receptors
3.1. Introduction
3.2. Drug-Receptor Interactions
     3.2.1. General Considerations
     3.2.2. Important Interactions (Forces) Involved in the Drug-Receptor Complex
          3.2.2.1. Covalent Bonds
          3.2.2.2. Ionic (or Electrostatic) Interactions
          3.2.2.3. Ion-Dipole and Dipole-Dipole Interactions
          3.2.2.4. Hydrogen Bonds
          3.2.2.5. Charge-Transfer Complexes
          3.2.2.6. Hydrophobic Interactions
          3.2.2.7. Cation-p Interaction
          3.2.2.8. Halogen Bonding
          3.2.2.9. van der Waals or London Dispersion Forces
          3.2.2.10. Conclusion
     3.2.3. Determination of Drug-Receptor Interactions
     3.2.4. Theories for Drug-Receptor Interactions
          3.2.4.1. Occupancy Theory
          3.2.4.2. Rate Theory
          3.2.4.3. Induced-Fit Theory
          3.2.4.4. Macromolecular Perturbation Theory
          3.2.4.5. Activation-Aggregation Theory
          3.2.4.6. The Two-State (Multistate) Model of Receptor Activation
     3.2.5. Topographical and Stereochemical Considerations
          3.2.5.1. Spatial Arrangement of Atoms
          3.2.5.2. Drug and Receptor Chirality
          3.2.5.3. Diastereomers
          3.2.5.4. Conformational Isomers
          3.2.5.5. Atropisomers
          3.2.5.6. Ring Topology
     3.2.6. Case History of the Pharmacodynamically Driven Design of a Receptor Antagonist: Cimetidine
     3.2.7. Case History of the Pharmacokinetically Driven Design of Suvorexant
3.3. General References
3.4. Problems
References
4. Enzymes
4.1. Enzymes as Catalysts
     4.1.1. What are Enzymes?
     4.1.2. How do Enzymes Work?
          4.1.2.1. Specificity of Enzyme-Catalyzed Reactions
               4.1.2.1.1. Binding Specificity
               4.1.2.1.2. Reaction Specificity
          4.1.2.2. Rate Acceleration
4.2. Mechanisms of Enzyme Catalysis
     4.2.1. Approximation
     4.2.2. Covalent Catalysis
     4.2.3. General Acid-Base Catalysis
     4.2.4. Electrostatic Catalysis
     4.2.5. Desolvation
     4.2.6. Strain or Distortion
     4.2.7. Example of the Mechanisms of Enzyme Catalysis
4.3. Coenzyme Catalysis
     4.3.1. Pyridoxal 5'-Phosphate
          4.3.1.1. Racemases
          4.3.1.2. Decarboxylases
          4.3.1.3. Aminotransferases (Formerly Transaminases)
          4.3.1.4. PLP-Dependent ß-Elimination
     4.3.2. Tetrahydrofolate and Pyridine Nucleotides
     4.3.3. Flavin
          4.3.3.1. Two-Electron (Carbanion) Mechanism
          4.3.3.2. Carbanion Followed by Two One-Electron Transfers
          4.3.3.3. One-Electron Mechanism
          4.3.3.4. Hydride Mechanism
     4.3.4. Heme
     4.3.5. Adenosine Triphosphate and Coenzyme A
4.4. Enzyme Catalysis in Drug Discovery
     4.4.1. Enzymatic Synthesis of Chiral Drug Intermediates
     4.4.2. Enzyme Therapy
4.5. General References
4.6. Problems
References
5. Enzyme Inhibition and Inactivation
5.1. Why Inhibit an Enzyme?
5.2. Reversible Enzyme Inhibitors
     5.2.1. Mechanism of Reversible Inhibition
     5.2.2. Selected Examples of Competitive Reversible Inhibitor Drugs
          5.2.2.1. Simple Competitive Inhibition
               5.2.2.1.1. Epidermal Growth Factor Receptor Tyrosine Kinase as a Target for Cancer
               5.2.2.1.2. Discovery and Optimization of EGFR Inhibitors
          5.2.2.2. Stabilization of an Inactive Conformation: Imatinib, an Antileukemia Drug
               5.2.2.2.1. The Target: Bcr-Abl, a Constitutively Active Kinase
               5.2.2.2.2. Lead Discovery and Modification
               5.2.2.2.3. Binding Mode of Imatinib to Abl Kinase
               5.2.2.2.4. Inhibition of Other Kinases by Imatinib
          5.2.2.3. Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa Drugs)
               5.2.2.3.1. Lead Discovery
               5.2.2.3.2. Lead Modification
               5.2.2.3.3. Mechanism of Action
     5.2.3. Transition State Analogs and Multisubstrate Analogs
          5.2.3.1. Theoretical Basis
          5.2.3.2. Transition State Analogs
               5.2.3.2.1. Enalaprilat
               5.2.3.2.2. Pentostatin
               5.2.3.2.3. Forodesine and DADMe-ImmH
               5.2.3.2.4. Multisubstrate Analogs
     5.2.4. Slow, T ight-Binding Inhibitors
          5.2.4.1. Theoretical Basis
          5.2.4.2. Captopril, Enalapril, Lisinopril, and Other Antihypertensive Drugs
               5.2.4.2.1. Humoral Mechanism for Hypertension
               5.2.4.2.2. Lead Discovery
               5.2.4.2.3. Lead Modification and Mechanism of Action
               5.2.4.2.4. Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors
          5.2.4.3. Lovastatin (Mevinolin) and Simvastatin, Antihypercholesterolemic Drugs
               5.2.4.3.1. Cholesterol and Its Effects
               5.2.4.3.2. Lead Discovery
               5.2.4.3.3. Mechanism of Action
               5.2.4.3.4. Lead Modification
          5.2.4.4. Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor and Antidiabetes Drug
     5.2.5. Case History of Rational Drug Design of an Enzyme Inhibitor: Ritonavir
          5.2.5.1. Lead Discovery
          5.2.5.2. Lead Modification
5.3. Irreversible Enzyme Inhibitors
     5.3.1. Potential of Irreversible Inhibition
     5.3.2. Affinity Labeling Agents
          5.3.2.1. Mechanism of Action
          5.3.2.2. Selected Affinity Labeling Agents
               5.3.2.2.1. Penicillins and Cephalosporins/Cephamycins
               5.3.2.2.2. Aspirin
     5.3.3. Mechanism-Based Enzyme Inactivators
          5.3.3.1. Theoretical Aspects
          5.3.3.2. Potential Advantages in Drug Design Relative to Affinity Labeling Agents
          5.3.3.3. Selected Examples of Mechanism-Based Enzyme Inactivators
               5.3.3.3.1. Vigabatrin, an Anticonvulsant Drug
               5.3.3.3.2. Eflornithine, an Antiprotozoal Drug and Beyond
               5.3.3.3.3. Tranylcypromine, an Antidepressant Drug
               5.3.3.3.4. Selegiline (l-Deprenyl) and Rasagiline: Antiparkinsonian Drugs
               5.3.3.3.5. 5-Fluoro-2'-deoxyuridylate, Floxuridine, and 5-Fluorouracil: Antitumor Drugs
5.4. General References
5.5. Problems
References
6. DNA-Interactive Agents
6.1. Introduction
     6.1.1. Basis for DNA-Interactive Drugs
     6.1.2. Toxicity of DNA-Interactive Drugs
     6.1.3. Combination Chemotherapy
     6.1.4. Drug Interactions
     6.1.5. Drug Resistance
6.2. DNA Structure and Properties
     6.2.1. Basis for the Structure of DNA
     6.2.2. Base Tautomerization
     6.2.3. DNA Shapes
     6.2.4. DNA Conformations
6.3. Classes of Drugs that Interact with DNA
     6.3.1. Reversible DNA Binders
          6.3.1.1. External Electrostatic Binding
          6.3.1.2. Groove Binding
          6.3.1.3. Intercalation and Topoisomerase-Induced DNA Damage
               6.3.1.3.1. Amsacrine, an Acridine Analog
               6.3.1.3.2. Dactinomycin, the Parent Actinomycin Analog
               6.3.1.3.3. Doxorubicin (Adriamycin) and Daunorubicin (Daunomycin), Anthracycline Antitumor Antibiotics
               6.3.1.3.4. Bis-intercalating Agents
     6.3.2. DNA Alkylators
          6.3.2.1. Nitrogen Mustards
               6.3.2.1.1. Lead Discovery
               6.3.2.1.2. Chemistry of Alkylating Agents
               6.3.2.1.3. Lead Modification
               6.3.2.2. Ethylenimines
               6.3.2.3. Methanesulfonates
               6.3.2.4. (+)-CC-1065 and Duocarmycins
               6.3.2.5. Metabolically Activated Alkylating Agents
                    6.3.2.5.1. Nitrosoureas
                    6.3.2.5.2. Triazene Antitumor Drugs
                    6.3.2.5.3. Mitomycin C
                    6.3.2.5.4. Leinamycin
     6.3.3. DNA Strand Breakers
          6.3.3.1. Anthracycline Antitumor Antibiotics
          6.3.3.2. Bleomycin
          6.3.3.3. Tirapazamine
          6.3.3.4. Enediyne Antitumor Antibiotics
               6.3.3.4.1. Esperamicins and Calicheamicins
               6.3.3.4.2. Dynemicin A
               6.3.3.4.3. Neocarzinostatin (Zinostatin)
          6.3.3.5. Sequence Specificity for DNA-Strand Scission
6.4. General References
6.5. Problems
References
7. Drug Resistance and Drug Synergism
7.1. Drug Resistance
     7.1.1. What is Drug Resistance?
     7.1.2. Mechanisms of Drug Resistance
          7.1.2.1. Altered Target Enzyme or Receptor
          7.1.2.2. Overproduction of the Target Enzyme or Receptor
          7.1.2.3. Overproduction of the Substrate or Ligand for the Target Protein
          7.1.2.4. Increased Drug-Destroying Mechanisms
          7.1.2.5. Decreased Prodrug-Activating Mechanism
          7.1.2.6. Activation of New Pathways Circumventing the Drug Effect
          7.1.2.7. Reversal of Drug Action
          7.1.2.8. Altered Drug Distribution to the Site of Action
7.2. Drug Synergism (Drug Combination)
     7.2.1. What is Drug Synergism?
     7.2.2. Mechanisms of Drug Synergism
          7.2.2.1. Inhibition of a Drug-Destroying Enzyme
          7.2.2.2. Sequential Blocking
          7.2.2.3. Inhibition of Targets in Different Pathways
          7.2.2.4. Efflux Pump Inhibitors
          7.2.2.5. Use of Multiple Drugs for the Same Target
7.3. General References
7.4. Problems
References
8. Drug Metabolism
8.1. Introduction
8.2. Synthesis of Radioactive Compounds
8.3. Analytical Methods in Drug Metabolism
     8.3.1. Sample Preparation
     8.3.2. Separation
     8.3.3. Identification
     8.3.4. Quantification
8.4. Pathways for Drug Deactivation and Elimination
     8.4.1. Introduction
     8.4.2. Phase I Transformations
          8.4.2.1. Oxidative Reactions
               8.4.2.1.1. Aromatic Hydroxylation
               8.4.2.1.2. Alkene Epoxidation
               8.4.2.1.3. Oxidations of Carbons Adjacent to sp2 Centers
               8.4.2.1.4. Oxidation at Aliphatic and Alicyclic Carbon Atoms
               8.4.2.1.5. Oxidations of Carbon-Nitrogen Systems
               8.4.2.1.6. Oxidations of Carbon-Oxygen Systems
               8.4.2.1.7. Oxidations of Carbon-Sulfur Systems
               8.4.2.1.8. Other Oxidative Reactions
               8.4.2.1.9. Alcohol and Aldehyde Oxidations
          8.4.2.2. Reductive Reactions
               8.4.2.2.1. Carbonyl Reduction
               8.4.2.2.2. Nitro Reduction
               8.4.2.2.3. Azo Reduction
               8.4.2.2.4. Azido Reduction
               8.4.2.2.5. Tertiary Amine Oxide Reduction
               8.4.2.2.6. Reductive Dehalogenation
          8.4.2.3. Carboxylation Reaction
          8.4.2.4. Hydrolytic Reactions
     8.4.3. Phase II Transformations: Conjugation Reaction
          8.4.3.1. Introduction
          8.4.3.2. Glucuronic Acid Conjugation
          8.4.3.3. Sulfate Conjugation
          8.4.3.4. Amino Acid Conjugation
          8.4.3.5. Glutathione Conjugation
          8.4.3.6. Water Conjugation
          8.4.3.7. Acetyl Conjugation
          8.4.3.8. Fatty Acid and Cholesterol Conjugation
          8.4.3.9. Methyl Conjugation
     8.4.4. Toxicophores and Reactive Metabolites (RMs)
     8.4.5. Hard and Soft (Antedrugs) Drugs
8.5. General References
8.6. Problems
References
9. Prodrugs and Drug Delivery Systems
9.1. Enzyme Activation of Drugs
     9.1.1. Utility of Prodrugs
          9.1.1.1. Aqueous Solubility
          9.1.1.2. Absorption and Distribution
          9.1.1.3. Site Specificity
          9.1.1.4. Instability
          9.1.1.5. Prolonged Release
          9.1.1.6. Toxicity
          9.1.1.7. Poor Patient Acceptability
          9.1.1.8. Formulation Problems
     9.1.2. Types of Prodrugs
9.2. Mechanisms of Drug Inactivation
     9.2.1. Carrier-Linked Prodrugs
          9.2.1.1. Carrier Linkages for Various Functional Groups
               9.2.1.1.1. Alcohols, Carboxylic Acids, and Related
               9.2.1.1.2. Amines and Amidines
               9.2.1.1.3. Sulfonamides
               9.2.1.1.4. Carbonyl Compounds
          9.2.1.2. Examples of Carrier-Linked Bipartite Prodrugs
               9.2.1.2.1. Prodrugs for Increased Water Solubility
               9.2.1.2.2. Prodrugs for Improved Absorption and Distribution
               9.2.1.2.3. Prodrugs for Site Specificity
               9.2.1.2.4. Prodrugs for Stability
               9.2.1.2.5. Prodrugs for Slow and Prolonged Release
               9.2.1.2.6. Prodrugs to Minimize Toxicity
               9.2.1.2.7. Prodrugs to Encourage Patient Acceptance
               9.2.1.2.8. Prodrugs to Eliminate Formulation Problems
          9.2.1.3. Macromolecular Drug Carrier Systems
               9.2.1.3.1. General Strategy
               9.2.1.3.2. Synthetic Polymers
               9.2.1.3.3. Poly(a-Amino Acids)
               9.2.1.3.4. Other Macromolecular Supports
          9.2.1.4. Tripartite Prodrugs
          9.2.1.5. Mutual Prodrugs (also called Codrugs)
     9.2.2. Bioprecursor Prodrugs
          9.2.2.1. Origins
          9.2.2.2. Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole
          9.2.2.3. Hydrolytic Activation
          9.2.2.4. Elimination Activation
          9.2.2.5. Oxidative Activation
               9.2.2.5.1. N- and O-Dealkylations
               9.2.2.5.2. Oxidative Deamination
               9.2.2.5.3. N-Oxidation
               9.2.2.5.4. S-Oxidation
               9.2.2.5.5. Aromatic Hydroxylation
               9.2.2.5.6. Other Oxidations
          9.2.2.6. Reductive Activation
               9.2.2.6.5. Nitro Reduction
          9.2.2.7. Nucleotide Activation
          9.2.2.8. Phosphorylation Activation
          9.2.2.9. Sulfation Activation
          9.2.2.10. Decarboxylation Activation
9.3. General References
9.4. Problems
References
Appendix
Index
 
 

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