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Preface | |
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Acknowledgements | |
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Abbreviations/Acronyms | |
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Biological Molecules | |
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Introduction | |
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Amino acids | |
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Introduction | |
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Structure | |
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Nomenclature | |
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Peptides and proteins | |
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Structure | |
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Carbohydrates | |
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The structure of monosaccharides | |
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The nomenclature of monosaccharides | |
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Glycosides | |
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Polysaccharides | |
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The nomenclature of polysaccharides | |
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Naturally occurring polysaccharides | |
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Lipids | |
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Introduction | |
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Fatty acids | |
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Acylglycerols (glycerides) | |
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Steroids | |
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Terpenes | |
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Phospholipids | |
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Glycolipids | |
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Nucleic acids | |
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Introduction | |
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DNA, structure and replication | |
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Genes and the human genome project | |
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RNA, structure and transcription | |
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Classification and function of RNA | |
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Questions | |
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An Introduction to Drugs and their Action | |
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Introduction | |
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What are drugs and why do we need new ones? | |
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Drug discovery and design, a historical outline | |
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Sources of drugs and lead compounds | |
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Natural sources | |
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Drug synthesis | |
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Market forces and 'me-too drugs' | |
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Classification of drugs | |
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Routes of administration, the pharmaceutical phase | |
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Introduction to drug action | |
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The pharmacokinetic phase | |
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Absorption | |
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Distribution | |
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Metabolism | |
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Elimination | |
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Bioavailability of a drug | |
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The pharmacodynamic phase | |
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Questions | |
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An Introduction to Drug Discovery | |
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Introduction | |
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Stereochemistry and drug design | |
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Structurally rigid groups | |
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Conformation | |
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Configuration | |
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Solubility and drug design | |
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The importance of water solubility | |
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Solubility and drug structure | |
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Salt formation | |
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The incorporation of water solubilizing groups in a structure | |
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The type of group | |
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Reversibly and irreversibly attached groups | |
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The position of the water solubilizing group | |
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Methods of introduction | |
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Questions | |
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The SAR and QSAR Approaches to Drug Design | |
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Structure-activity relationships (SARs) | |
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Changing size and shape | |
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Introduction of new substituents | |
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The introduction of a group in an unsubstituted position | |
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The introduction of a group by replacing an existing group | |
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Quantitative structure-activity relationships (QSARs) | |
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Lipophilicity | |
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Partition coefficients (P) | |
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Lipophilic substitution constants ([pi]) | |
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Electronic effects | |
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The Hammett constant ([sigma]) | |
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Steric effects | |
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The Taft steric parameter (E[subscript s]) | |
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Molar refractivity (MR) | |
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Other parameters | |
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Hansch analysis | |
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Craig plots | |
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The Topliss decision tree | |
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Questions | |
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Computer Aided Drug Design | |
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Introduction | |
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Molecular modelling methods | |
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Computer graphics | |
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Molecular mechanics | |
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Creating a molecular model using molecular mechanics | |
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Molecular dynamics | |
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Conformational analysis | |
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Quantum mechanics | |
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Docking | |
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Questions | |
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Combinatorial Chemistry | |
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Introduction | |
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The design of combinatorial syntheses | |
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The general techniques used in combinatorial synthesis | |
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The solid support method | |
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Parallel synthesis | |
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Furka's mix and split technique | |
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Encoding methods | |
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Sequential chemical tagging methods | |
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Still's binary code tag system | |
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Computerized tagging | |
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Combinatorial synthesis in solution | |
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Screening and deconvolution | |
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Questions | |
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Selected Examples of Drug Action at some Common Target Areas | |
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Introduction | |
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Examples of drugs that disrupt cell membranes and walls | |
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Antifungal agents | |
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Azoles | |
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Allylamines | |
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Phenols | |
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Antibacterial apents | |
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Ionophoric antibiotic action | |
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Cell wall synthesis inhibition | |
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Drugs that target enzymes | |
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Reversible inhibihors | |
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Irreversible inhibition | |
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Transition state inhibitors | |
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Drugs that target receptors | |
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Agonists | |
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Antagonists | |
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Partial agonists | |
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Drugs that target nucleic acids | |
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Antimetabolites | |
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Enzyme inhibitors | |
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Intercalation agents | |
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Alkylating agents | |
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Antisense drugs | |
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Chain cleaving agents | |
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Antiviral drugs | |
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Nucleic acid synthesis inhibitors | |
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Host cell penetration inhibitors | |
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Inhibitors of viral protein synthesis | |
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Questions | |
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Pharmacokinetics | |
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Introduction to pharmacokinetics | |
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General classification of pharmacokinetic properties | |
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Pharmacokinetics and drug design | |
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Pharmacokinetic models | |
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Intravascular administration | |
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Intravenous injection (IV bolus) | |
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Clearance and its significance | |
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Intravenous infusion | |
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Extravascular administration | |
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Single oral dose | |
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The calculation of t[subscript max] and C[subscript max] | |
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Repeated oral doses | |
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The use of pharmacokinetics in drug design | |
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Questions | |
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Drug Metabolism | |
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Introduction | |
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The stereochemistry of drug metabolism | |
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Biological factors affecting metabolism | |
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Environmental factors affecting metabolism | |
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Species and metabolism | |
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Secondary pharmacological implications of metabolism | |
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Sites of action | |
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Phase I metabolic reactions | |
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Oxidation | |
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Reduction | |
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Hydrolysis | |
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Hydration | |
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Other Phase I reactions | |
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Phase II metabolic routes | |
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Pharmacokinetics of metabolites | |
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Drug metabolism and drug design | |
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Prodrugs | |
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Bioprecursor prodrugs | |
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Carrier prodrugs | |
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The design of prodrug systems for specific purposes | |
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Improving absorption and transport through membranes | |
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Improving patient acceptance | |
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Slow release | |
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Site specificity | |
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Minimizing side effects | |
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Questions | |
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An Introduction to Lead and Analogue Syntheses | |
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Introduction | |
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Asymmetry in syntheses | |
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The use of non-stereoselective reactions to produce stereospecific centres | |
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The use of stereoselective reactions to produce stereospecific centres | |
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General methods of asymmetric synthesis | |
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Methods that use catalysts to obtain stereoselectivity | |
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Methods that do not use catalysts to obtain stereoselectivity | |
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Designing organic syntheses | |
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An introduction to the disconnection approach | |
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Questions | |
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Drug Development and Production | |
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Introduction | |
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Chemical development | |
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Chemical engineering issues | |
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Chemical plant, health and safety considerations | |
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Synthesis quality control | |
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A case study | |
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Pharmacological and toxicological testing | |
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Drug metabolism and pharmacokinetics | |
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Formulation development | |
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Production and quality control | |
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Patent protection | |
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Regulation | |
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Questions | |
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Appendix | |
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Sickle-cell anaemia | |
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Bacteria | |
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Cell membranes | |
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Receptors | |
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Transfer through membranes | |
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Regression analysis | |
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Enzymes | |
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Prostaglandins | |
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Cancer | |
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Viruses | |
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Blood-brain barrier | |
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Enzyme structure and species | |
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Answers to Questions | |
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Selected Further Reading | |
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Index | |