Medicinal Chemistry A Molecular and Biochemical Approach

by Nogrady, Thomas; Weaver, Donald F.

• ISBN13: 9780195104561
• ISBN10: 0195104560
• eBook ISBN(s): 9780190282967
• Additional ISBN(s): 9780195053692, 9780195104554
• Edition: 3rd
• Format: Paperback
• Copyright: 2005-08-11
• Publisher: Oxford University Press
• More Book Details

Summary

Fully updated and rewritten by a basic scientist who is also a practicing physician, the third edition of this popular textbook remains comprehensive, authoritative and readable. Taking a receptor-based, target-centered approach, it presents the concepts central to the study of drug action ina logical, mechanistic way grounded on molecular and biochemical principles. Students of pharmacy, chemistry and pharmacology, as well as researchers interested in a better understanding of drug design, will find this book an invaluable resource. Starting with an overview of basicprinciples, Medicinal Chemistry examines the properties of drug molecules, the characteristics of drug receptors, and the nature of drug-receptor interactions. Then it systematically examines the various families of receptors involved in human disease and drug design. The first three classes ofreceptors are related to endogenous molecules: neurotransmitters, hormones and immunomodulators. Next, receptors associated with cellular organelles (mitochondria, cell nucleus), endogenous macromolecules (membrane proteins, cytoplasmic enzymes) and exogenous pathogens (viruses, bacteria) areexamined. Through this evaluation of receptors, all the main types of human disease and all major categories of drugs are considered. There have been many changes in the third edition, including a new chapter on the immune system. Because of their increasingly prominent role in drugdiscovery, molecular modeling techniques, high throughput screening, neuropharmacology and genetics/genomics are given much more attention. The chapter on hormonal therapies has been thoroughly updated and re-organized. Emerging enzyme targets in drug design (e.g. kinases, caspases) are discussed,and recent information on voltage-gated and ligand-gated ion channels has been incorporated. The sections on antihypertensive, antiviral, antibacterial, anti-inflammatory, antiarrhythmic, and anticancer drugs, as well as treatments for hyperlipidemia and peptic ulcer, have been substantiallyexpanded. One new feature will enhance the book's appeal to all readers: clinical-molecular interface sections that facilitate understanding of the treatment of human disease at a molecular level.

Author Biography

Thomas Nogrady, PhD, is Emeritus Professor of Medicinal Chemistry at Concordia University, Montreal, Quebec, Canada Donald F. Weaver, MD, PhD, FRCP(C), is the Canada Research Chair and Professor of Medicine and Chemistry at Dalhousie University, Halifax, Nova Scotia, Canada

Table of Contents

I GENERAL MOLECULAR PRINCIPLES OF DRUG DESIGN
Introduction to Part I	5	(4)
Drug Design: A Conceptual Approach	5	(2)
Drug Design: A Practical Approach	7	(1)
Drug Design: The Humanitarian Approach	8	(1)
1. Basic Principles of Drug Design I-Drug Molecules: Structure and Properties	9	(58)
1.1 Definition and Properties of a Drug Molecule	9	(15)
1.2 Physicochemical Properties of Drug Molecules	24	(8)
1.3 Shape (Geometric, Conformational, Topological, and Steric) Properties of Drug Molecules	32	(4)
1.4 Stereochemical Properties of Drug Molecules	36	(4)
1.5 Electronic Properties of Drug Molecules	40	(3)
1.6 Predicting the Properties of Drug Molecules: Quantum Mechanics and Molecular Mechanics	43	(20)
Selected References	63	(4)
2. Basic Principles of Drug Design II-Receptors: Structure and Properties	67	(39)
2.1 The Receptor Concept and its History	67	(1)
2.2 The Nature of Receptors and Criteria for Receptor Identity	68	(1)
2.3 Definitions of Drug-Receptor Binding Interactions	69	(6)
2.4 Definitions of Classical Binding Terms for Drug-Receptor Interactions	75	(3)
2.5 Classical Theories of Drug-Receptor Binding Interactions	78	(3)
2.6 Experimental Quantification of Drug-Receptor Binding Interactions	81	(3)
2.7 General Molecular Concepts of Drug Receptor Action	84	(6)
2.8 Receptor Action: Regulation, Metabolism, and Dynamics	90	(2)
2.9 Receptor Types as Determined by Molecular Mode of Action	92	(1)
2.10 Receptor Action: Mechanisms in Receptor Signal Transduction	93	(3)
2.11 Selecting a Receptor Appropriate for Drug Design	96	(5)
2.12 The Clinical-Molecular Interface: The Concept of Rational Polypharmacy	101	(2)
Selected References	103	(3)
3. Basic Principles of Drug Design III-Designing Drug Molecules to Fit Receptors	106	(79)
3.1 Overall Strategy: The Multiphore Method of Drug Design	106	(2)
3.2 Identification of a Lead Compound	108	(20)
3.3 Synthesis of a Lead Compound	128	(6)
3.4 Optimizing the Lead Compound: The Pharmacodynamic Phase	134	(12)
3.5 Optimizing the Lead Compound: Pharmacokinetic and Pharmaceutical Phases	146	(13)
3.6 From Lead Discovery to Clinical Trials: The Concept of a "Useful Drug"	159	(4)
Selected References	163	(3)
Appendix 3.1: Basic Reactions for Drug Molecule Synthesis	166	(19)
II BIOCHEMICAL CONSIDERATIONS IN DRUG DESIGN: FROM DRUGGABLE TARGETS TO DISEASES
Introduction to Part II	185	(8)
The Physiological Systems Approach	186	(1)
The Pathological Process Approach	186	(2)
The Molecular Messenger and Nonmessenger Target System	188	(5)
4. Messenger Targets for Drug Action I: Neurotransmitters and Their Receptors	193	(117)
4.1 Overview of Relevant Neuroanatomy and Neurophysiology	193	(11)
4.2 Acetylcholine and the Cholinergic Receptors	204	(14)
4.3 Norepinephrine and the Adrenergic Receptors	218	(20)
4.4 Dopamine and the Dopaminergic Receptors	238	(11)
4.5 Serotonin and the Serotonergic Receptors	249	(11)
4.6 Histamine and the Histamine Receptors	260	(10)
4.7 Inhibitory Amino Acid Neurotransmitters: γ-Aminobutyric Acid (GABA)	270	(11)
4.8 Inhibitory Amino Acid Neurotransmitters: Glycine	281	(2)
4.9 Excitatory Amino Acid Neurotransmitters: Glutamate	283	(5)
4.10 Large-Molecule Neurotransmitters: Peptides	288	(3)
4.11 Small-Molecule Neurotransmitters: Gases (Nitric Oxide, Carbon Monoxide)	291	(5)
4.12 Neuromodulators: Taurine and β-Alanine	296	(1)
4.13 Purinergic Neuromodulation and the Adenosine Receptors	297	(2)
Selected References	299	(11)
5. Messenger Targets for Drug Action II: Hormones and Their Receptors	310	(76)
5.1 Overview of Relevant Anatomy and Physiology of Hormones	310	(2)
5.2 Steroid Hormones: Introduction	312	(1)
5.3 Steroid Hormones: Receptor Biochemistry	312	(2)
5.4 Steroid Hormones: Structure and Conformation of Agonists and Antagonists	314	(1)
5.5 Steroid Hormones: Steroid Biosynthesis	315	(1)
5.6 Steroid Hormones: Cholesterol as a Biosynthetic Precursor	316	(4)
5.7 Steroid Hormones: Sex Hormones-Introduction	320	(1)
5.8 Steroid Hormones: Sex Hormones-Estrogens	321	(4)
5.9 Steroid Hormones: Sex Hormones-Progestins (Gestagens)	325	(3)
5.10 Steroid Hormones: Sex Hormones-Androgens	328	(4)
5.11 Steroid Hormones: Adrenocorticoids (Adrenal Steroids)-Overview	332	(1)
5.12 Steroid Hormones: Adrenocorticoids-Glucocorticoids	332	(5)
5.13 Steroid Hormones: Adrenocorticoids-Mineralocorticoids	337	(1)
5.14 Peptide Hormones: Introduction	338	(1)
5.15 Peptide Hormones of the Brain	338	(8)
5.16 Peptide Hormones of the Anterior Pituitary	346	(2)
5.17 Peptide Hormones of the Posterior Pituitary	348	(2)
5.18 Peptide Hormones of the Opiate System	350	(9)
5.19 Peptide Hormones of the Thyroid and Parathyroid Glands	359	(5)
5.20 Peptide Hormones of the Pancreas: Insulin and Glucagon	364	(7)
5.21 Peptide Hormones of the Kidney (Renin-Angiotensin System)	371	(5)
5.22 Peptide Hormones of the Heart (Natriuretic Factors)	376	(2)
5.23 Peptide Hormones and the Design of Drugs for Hypertension	378	(3)
5.24 Peptide and Steroid Hormones as Starting Points in Drug Design	381	(1)
Selected References	382	(4)
6. Messenger Targets for Drug Action III: Immunomodulators and Their Receptors	386	(20)
6.1 Overview of the Immune System as a Source of Drug Targets	386	(6)
6.2 Design of Immunosuppressive Drugs	392	(6)
6.3 Design of Immunomodulating Drugs	398	(5)
6.4 The Clinical-Molecular Interface: Collagen Diseases	403	(2)
Selected References	405	(1)
7. Nonmessenger Targets for Drug Action I: Endogenous Cellular Structures	406	(59)
7.1 Cellular Structures: Relevant Anatomy and Physiology	406	(3)
7.2 Targeting Cell Membrane Structures: Lipid Component	409	(3)
7.3 Targeting Cell Membrane Structures: Protein Component	412	(1)
7.4 Targeting Cell Membrane Proteins: Voltage-Gated Ion Channels	413	(19)
7.5 Targeting Cell Membrane Proteins: Ligand-Gated Ion Channels	432	(1)
7.6 Targeting Cell Membrane Proteins: Transmembrane Transporter Proteins	433	(6)
7.7 Targeting Cellular Cytoplasmic Structures	439	(2)
7.8 Targeting Cell Nucleus Structures	441	(22)
Selected References	463	(2)
8. Nonmessenger Targets for Drug Action II: Endogenous Macromolecules	465	(78)
8.1 Endogenous Macromolecules: Relevant Biochemistry	465	(18)
8.2 Proteins as Drugs and Drug Design Targets: Enzymes	483	(30)
8.3 Proteins as Drugs and Drug Design Targets: Non-Enzymes	513	(4)
8.4 Nucleic Acids as Drugs and Drug Design Targets	517	(2)
8.5 Lipids as Drugs and Drug Design Targets	519	(9)
8.6 Carbohydrates as Drugs and Drug Design Targets	528	(1)
8.7 Heterocycles as Drugs and Drug Design Targets	529	(3)
8.8 Inorganic Substances as Drugs and Drug Design Targets	532	(6)
Selected References	538	(5)
9. Nonmessenger Targets for Drug Action III: Exogenous Pathogens and Toxins	543	(58)
9.1 Exogenous Pathogens as Targets for Drug Design	543	(3)
9.2 Drug Design Targeting Prions	546	(1)
9.3 Drug Design Targeting Viruses	547	(12)
9.4 Drug Design Targeting Bacteria	559	(22)
9.5 Drug Design Targeting Fungi	581	(3)
9.6 Drug Design Targeting Parasites	584	(7)
9.7 The Clinical-Molecular Interface: Pneumonia	591	(1)
9.8 The Clinical-Molecular Interface: Meningitis and Encephalitis	592	(1)
9.9 Drug Design of Therapies and Antidotes for Toxins	593	(3)
Selected References	596	(5)
Appendix: Drugs Arranged by Pharmacological Activity	601	(28)
Index	629