Medicinal Chemistry: A Molecular and Biochemical Approach

Contents......Page 11
I: GENERAL MOLECULAR PRINCIPLES OF DRUG DESIGN......Page 19
Drug Design: A Conceptual Approach......Page 21
Drug Design: A Practical Approach......Page 23
Drug Design: The Humanitarian Approach......Page 24
1.1 Definition and Properties of a Drug Molecule......Page 25
1.2 Physicochemical Properties of Drug Molecules......Page 40
1.3 Shape (Geometric, Conformational, Topological, and Steric) Properties of Drug Molecules......Page 48
1.4 Stereochemical Properties of Drug Molecules......Page 52
1.5 Electronic Properties of Drug Molecules......Page 56
1.6 Predicting the Properties of Drug Molecules: Quantum Mechanics and Molecular Mechanics......Page 59
Selected References......Page 79
2.1 The Receptor Concept and its History......Page 83
2.2 The Nature of Receptors and Criteria for Receptor Identity......Page 84
2.3 Definitions of Drug–Receptor Binding Interactions......Page 85
2.4 Definitions of Classical Binding Terms for Drug–Receptor Interactions......Page 91
2.5 Classical Theories of Drug–Receptor Binding Interactions......Page 94
2.6 Experimental Quantification of Drug–Receptor Binding Interactions......Page 97
2.7 General Molecular Concepts of Drug Receptor Action......Page 100
2.8 Receptor Action: Regulation, Metabolism, and Dynamics......Page 106
2.9 Receptor Types as Determined by Molecular Mode of Action......Page 108
2.10 Receptor Action: Mechanisms in Receptor Signal Transduction......Page 109
2.11 Selecting a Receptor Appropriate for Drug Design......Page 112
2.12 The Clinical–Molecular Interface: The Concept of Rational Polypharmacy......Page 117
Selected References......Page 119
3.1 Overall Strategy: The Multiphore Method of Drug Design......Page 122
3.2 Identification of a Lead Compound......Page 124
3.3 Synthesis of a Lead Compound......Page 144
3.4 Optimizing the Lead Compound: The Pharmacodynamic Phase......Page 150
3.5 Optimizing the Lead Compound: Pharmacokinetic and Pharmaceutical Phases......Page 162
3.6 From Lead Discovery to Clinical Trials: The Concept of a “Useful Drug”......Page 175
Selected References......Page 179
Appendix 3.1: Basic Reactions for Drug Molecule Synthesis......Page 182
II: BIOCHEMICAL CONSIDERATIONS IN DRUG DESIGN: FROM DRUGGABLE TARGETS TO DISEASES......Page 199
Introduction to Part II......Page 201
The Pathological Process Approach......Page 202
The Molecular Messenger and Nonmessenger Target System......Page 204
4.1 Overview of Relevant Neuroanatomy and Neurophysiology......Page 209
4.2 Acetylcholine and the Cholinergic Receptors......Page 220
4.3 Norepinephrine and the Adrenergic Receptors......Page 234
4.4 Dopamine and the Dopaminergic Receptors......Page 254
4.5 Serotonin and the Serotonergic Receptors......Page 265
4.6 Histamine and the Histamine Receptors......Page 276
4.7 Inhibitory Amino Acid Neurotransmitters: γ-Aminobutyric Acid (GABA)......Page 286
4.8 Inhibitory Amino Acid Neurotransmitters: Glycine......Page 297
4.9 Excitatory Amino Acid Neurotransmitters: Glutamate......Page 299
4.10 Large-Molecule Neurotransmitters: Peptides......Page 304
4.11 Small-Molecule Neurotransmitters: Gases (Nitric Oxide, Carbon Monoxide)......Page 307
4.12 Neuromodulators: Taurine and β-Alanine......Page 312
4.13 Purinergic Neuromodulation and the Adenosine Receptors......Page 313
Selected References......Page 315
5.1 Overview of Relevant Anatomy and Physiology of Hormones......Page 326
5.3 Steroid Hormones: Receptor Biochemistry......Page 328
5.4 Steroid Hormones: Structure and Conformation of Agonists and Antagonists......Page 330
5.5 Steroid Hormones: Steroid Biosynthesis......Page 331
5.6 Steroid Hormones: Cholesterol as a Biosynthetic Precursor......Page 332
5.7 Steroid Hormones: Sex Hormones—Introduction......Page 336
5.8 Steroid Hormones: Sex Hormones—Estrogens......Page 337
5.9 Steroid Hormones: Sex Hormones—Progestins (Gestagens)......Page 341
5.10 Steroid Hormones: Sex Hormones—Androgens......Page 344
5.12 Steroid Hormones: Adrenocorticoids—Glucocorticoids......Page 348
5.13 Steroid Hormones: Adrenocorticoids—Mineralocorticoids......Page 353
5.15 Peptide Hormones of the Brain......Page 354
5.16 Peptide Hormones of the Anterior Pituitary......Page 362
5.17 Peptide Hormones of the Posterior Pituitary......Page 364
5.18 Peptide Hormones of the Opiate System......Page 366
5.19 Peptide Hormones of the Thyroid and Parathyroid Glands......Page 375
5.20 Peptide Hormones of the Pancreas: Insulin and Glucagon......Page 380
5.21 Peptide Hormones of the Kidney (Renin–Angiotensin System)......Page 387
5.22 Peptide Hormones of the Heart (Natriuretic Factors)......Page 392
5.23 Peptide Hormones and the Design of Drugs for Hypertension......Page 394
5.24 Peptide and Steroid Hormones as Starting Points in Drug Design......Page 397
Selected References......Page 398
6.1 Overview of the Immune System as a Source of Drug Targets......Page 402
6.2 Design of Immunosuppressive Drugs......Page 408
6.3 Design of Immunomodulating Drugs......Page 414
6.4 The Clinical–Molecular Interface: Collagen Diseases......Page 419
Selected References......Page 421
7.1 Cellular Structures: Relevant Anatomy and Physiology......Page 422
7.2 Targeting Cell Membrane Structures: Lipid Component......Page 425
7.3 Targeting Cell Membrane Structures: Protein Component......Page 428
7.4 Targeting Cell Membrane Proteins: Voltage-Gated Ion Channels......Page 429
7.5 Targeting Cell Membrane Proteins: Ligand-Gated Ion Channels......Page 448
7.6 Targeting Cell Membrane Proteins: Transmembrane Transporter Proteins......Page 449
7.7 Targeting Cellular Cytoplasmic Structures......Page 455
7.8 Targeting Cell Nucleus Structures......Page 457
Selected References......Page 479
8.1 Endogenous Macromolecules: Relevant Biochemistry......Page 481
8.2 Proteins as Drugs and Drug Design Targets: Enzymes......Page 499
8.3 Proteins as Drugs and Drug Design Targets: Non-Enzymes......Page 529
8.4 Nucleic Acids as Drugs and Drug Design Targets......Page 533
8.5 Lipids as Drugs and Drug Design Targets......Page 535
8.6 Carbohydrates as Drugs and Drug Design Targets......Page 544
8.7 Heterocycles as Drugs and Drug Design Targets......Page 545
8.8 Inorganic Substances as Drugs and Drug Design Targets......Page 548
Selected References......Page 554
9.1 Exogenous Pathogens as Targets for Drug Design......Page 559
9.2 Drug Design Targeting Prions......Page 562
9.3 Drug Design Targeting Viruses......Page 563
9.4 Drug Design Targeting Bacteria......Page 575
9.5 Drug Design Targeting Fungi......Page 597
9.6 Drug Design Targeting Parasites......Page 600
9.7 The Clinical–Molecular Interface: Pneumonia......Page 607
9.8 The Clinical–Molecular Interface: Meningitis and Encephalitis......Page 608
9.9 Drug Design of Therapies and Antidotes for Toxins......Page 609
Selected References......Page 612
Appendix: Drugs Arranged by Pharmacological Activity......Page 617
A......Page 645
B......Page 647
C......Page 648
D......Page 650
E......Page 651
F......Page 652
H......Page 653
I......Page 654
L......Page 655
M......Page 656
N......Page 657
O......Page 658
P......Page 659
R......Page 661
S......Page 662
T......Page 663
U......Page 664
Z......Page 665