Basic Concepts in Medicinal Chemistry

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