Cover
Half Title
Basic Concepts in Medicinal Chemistry
Copyright
Dedication
Table of Contents
Acknowledgments
Preface
Abbreviations Used in This Text
1. Introduction
Review of Selected Nomenclature and Numbering
Orbital Hybridization and Bond Formation
Numbering of Alicyclic Rings
Designation of Aromatic Ring Positions
Numbering of Heterocyclic Rings
Numbering of Sugars
Alpha (α), Beta (β), and Omega (ω) Designations
Stereochemical Designations
Steroid Nomenclature
Peptide Designations
Nucleic Acid Nomenclature
References Consulted and Recommended
References
2. Functional Group Characteristics and Roles
What is a Functional Group?
Definitions
An Exclusive Interview with Some Functional Groups
Chemical Properties of Functional Groups
Electronic Effects
Electron Donating Functional Groups
Electron Withdrawing Functional Groups
Nucleophilic and Electrophilic Functional Groups
Water-Soluble Functional Groups
Solubility Effects
Lipid-Soluble Functional Groups
Steric Effects
Increased Selectivity
Enhanced Binding Interactions
Alteration of Metabolism
Final Considerations for Functional Groups on Drug Molecules
A Review of Functional Groups Present on Amino Acids
A Rerview of Functional Groups Present on DNA and RNA
Structural Analysis Checkpoint
Introduction to This Feature
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Review Questions
3. Identifying Acidic and Basic Functional Groups
Acidic Functional Groups
Carboxylic Acids
β-Dicarbonyl Groups
Sulfonamides and Sulfonylureas
Tetrazoles
Phenols
Definitions
What About Aliphatic Hydroxyl Groups?
Thiols
Sulfates, Phosphates, and Phosphonates
Basic Functional Groups
Back to General Chemistry
Aliphatic and Alicyclic Amines
Aromatic Amines
Imines and Hydrazines
Amidines and Guanidines
Nitrogen Containing Aromatic Heterocycles
Additional Nitrogen Containing Groups
Functional Groups Versus Drug Molecules
The Therapeutic Significance of the Acid/Base Nature of Drug Molecules
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Review Questions
4. Solving pH and pKa Problems
Defining pH and pKa
The Henderson-Hasselbalch Equation
Derivation of the Henderson-Hasselbalch Equation
Solving pH and pKa Problems
Solving Qualitative pH and pKa Problems Using the Henderson-Hasselbalch Equation
Solving Qualitative pH and pKa Problems Without the Henderson-Hasselbalch Equation
Scenario 1: pH Is Equal to the pKa
Scenario 2: pH Is Greater Than the pKa
Scenario 3: pH Is Less Than the pKa
Key Points Regarding All Three Scenarios
Calculating the Percent Ionization of a Functional Group
Solving Quantitative pH and pKa Problems
Calculating the pH of an Environment
Calculating the pKa of a Functional Group
The Rule of Nines
Sample Problem
Other Uses for the Rule of Nines
The Importance of pH and pKa in Drug Therapy
Outline of Therapeutic Examples
The Influence on the Solubility of a Drug Molecule
The Influence on the Duration of Action for a Drug Molecule
The Influence on Drug Binding Interactions
Ionization and Chemical Antagonism
Drug Interactions Based on pH and/or pKa Changes
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Review Questions
5. Salts and Solubility
What is a Salt?
Application to Drug Molecules
Inorganic Salts
Organic Salts
Water-Soluble Organic Salts
Lipid-Soluble Organic Salts
Similarities Among Organic Salts and Esters
Organic Salts and Drug Interactions
Using Names of Salts to Identify Acidic and Basic Drug Molecules
Solubility and Partition Coefficients
Analyzing a Drug Molecule for Its Water- and Lipid-Soluble Components
Important Skills to Master
A Balance Between Water and Lipid Solubility
Strategies for Optimizing the Desired Water or Lipid Solubility
Strategy 1: Use Inorganic and Organic Salts
Strategy 2: Convert the Parent Drug Molecule to a Water- or Lipid-Soluble Ester Prodrug
Strategy 3: Add or Alter Functional Groups
Factors Affecting the Oral Absorption of Drug Molecules
The Influence of Solubility on Drug Metabolism
A Summary of the Advantages of Enhancing Either Water or Lipid Solubility
Therapeutic Advantages of Enhancing Water Solubility
Therapeutic Advantages of Enhancing Lipid Solubility
Checkpoint Drug 2: Elamipretide
Review Questions
6. Drug Binding Interactions
Covalent Bonds
Concerns With the Use of Covalent Bonds
Specific Types of Covalent Bonds
Alkylation
Acylation
Phosphorylation
Rearrangement Reactions
Noncovalent Bonds
Ionic Bonds
Dipole Interactions
Ion–Dipole and Dipole–Dipole Interactions
Application of Concepts
Hydrogen Bonds
Summary of the Advantages of Hydrogen Bonds
van der Waals Interactions
Hydrophobic Effects (aka Hydrophobic Interactions)
Additional Aromatic Interactions
Summary of Biological Targets and Drug Binding Interactions
Chelation and Complexation
Summary of Key Concepts for Noncovalent Drug Binding Interactions
Review Questions
7. Stereochemistry and Drug Action
Chirality and Asymmetric Carbon Atoms
Enantiomers
Chemical and Physical Properties
Designations for Enantiomers and Chiral Centers
Pharmacological and Therapeutic Differences Between Enantiomers
Diastereomers
Geometric Isomers
Pharmacological and Therapeutic Differences Between Diastereomers and Geometric Isomers
Conformational Isomers
Terminology
Preferred Conformation
Active Conformation
Benefits of Conformational Restriction
Review Questions
8. Drug Metabolism
General Concepts of Drug Metabolism
Phase I Metabolism: Oxidation
The Cytochrome P450 (CYP450) Family of Enzymes
Other Enzymes Involved in Oxidative Transformations
Oxidation of Hydrocarbon Rings and Chains
Oxidation of Aromatic Rings/Aromatic Hydroxylation
Oxidation of Alkenes
Oxidation of Carbon Atoms Adjacent to sp2 Hybridized Centers
Oxidation of Aliphatic and Alicyclic Carbon Atoms
Oxidation of Amines, Amides, and Aromatic Nitrogen Atoms
Oxidative Deamination
Oxidative N-Dealkylation
N-Oxidation
Oxidation of Functional Groups with Carbon-Oxygen Bonds
Oxidation of Functional Groups Containing Sulfur Atoms
Oxidative Dehalogenation
Phase I Metabolism: Reduction
Reduction of Aldehydes and Ketones
Reduction of Azo and Nitro Groups
Miscellaneous Reductions
Phase I Metabolism: Hydrolysis
Summary of Phase I Metabolism
Phase II Metabolism: Conjugation
Glucuronic Acid Conjugation
Sulfate Conjugation
Amino Acid Conjugation
Glutathione Conjugation
Acetylation
Methylation
Summary of Phase II Metabolism
Factors That Affect Drug Metabolism
Summary of the key Concept Governing Metabolic Transformations
Checkpoint Drug 1: Venetoclax
References
Structural Analysis Checkpoint
Checkpoint Drug 2: Elamipretide
Review Questions
9. Structure Activity Relationships and Basic Concepts in Drug Design
Structure Activity Relationships
Overview: What Is Meant by the Term Structure Activity Relationship
The “Why” or “How” Component of an SAR Statement
Structure Activity Relationships and Pharmacological Activity
Examples of Structure Activity Relationships
Structure Activity Relationships and Binding Interactions
Structure Activity Relationships and Absorption, Distribution, Metabolism, and Excretion
Structure Activity Relationships and Drug Interactions and Adverse Drug Reactions
Basic Concept in Molecular Modification
Conformational Restriction
Variation of Functional Groups
Isosteres and Bioisosteres
Application Question
Classic Isosteres
Nonclassical Isosteres
Homologation
Chain Branching
The Conversion of an Active Drug to a Prodrug
Summary
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Insulin A chain SAR:
Insulin B chain SAR:
Review Questions
10. Whole Molecule Drug Evaluation
Aliskiren (Level 1)
Aripiprazole (Level 1)
Cefprozil (Level 1)
Levonorgestrel (Level 3)
Montelukast and Zafirlukast
Nadolol and Other β-Adrenergic Antagonists (Level 3)
Ofloxacin (Level 1)
Pravastatin and Fluvastatin (Level 2)
Quinapril (Level 1)
Saquinavir and Other Human Immunodeficiency Virus Protease Inhibitors (Level 3)
Sorafenib (Level 2)
Zanamivir and Oseltamivir (Level 2)
Appendix. Answers to Chapter Questions
Chapter 2
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Chapter 3
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Chapter 4
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Review Questions
Answer for the Acidic Functional Group (Dasolampanel):
Answer for the Basic Functional Group (Dasolampanel):
Answer for Acidic Functional Group (Carboxylic Acid)
Answer for Basic Functional Group (Secondary Amine/Piperazine)
Chapter 5
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Chapter 6
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Chapter 7
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Chapter 8
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Review Questions
Chapter 9
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
Checkpoint Drug 2: Elamipretide
Review Questions
Chapter 10
Aliskiren (Level 1)
Aripiprazole (Level 1)
Cefprozil (Level 1)
Levonorgestrel (Level 3)
Montelukast and Zafirlukast (Level 2)
Pathway B (Aromatic Oxidation): Phase I; Yes
Pathway C (Hydrolysis): Phase I; Yes
Pathway D (Oxidative O-Dealkylation): Phase I; Yes
Pathway E (Benzylic Oxidation): Phase I; Yes
Nadolol and Other a-Adrenergic Antagonists (Level 3)
Ofloxacin (Level 1)
Pravastatin and Fluvastatin (Level 2)
Quinapril (Level 1)
Saquinavir and Other Human Immunodeficiency Virus Protease Inhibitors (Level 3
Sorafenib (Level 2)
Zanamivir and Oseltamivir (Level 2)
Index