Ariëns Drug Design

Medicinal Chemistry: A Series of Monographs, Vol. 8
1. Auflage 2013
ISBN: 978-1-4832-1610-2
Verlag: Elsevier Science & Techn.
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 440 Seiten, Web PDF

Drug Design, Volume VIII covers a critical review and new extensions of quantitative methods in drug design, the design of particular types of agents, such as synthetic sweeteners, and selective ion binding compounds. The book discusses the advances in the methodology of quantitative drug design; the application of pattern recognition to drug design; and the design of controlled drug delivery systems. The text also describes the use of receptor binding as a tool in the development of new bioactive steroids; the design of synthetic sweeteners; and the prospective assessment of environmental effects of chemicals. The design of selective ion binding macrocyclic compounds and their biological applications are also encompassed. Chemists, pharmacologists, biochemists, and people involved in drug design and manufacture will find the book invaluable.

Autoren/Hrsg.

Ariëns, E. J.

Inhaltsverzeichnis

1;Front Cover;1
2;Drug Design;4
3;Copyright Page;5
4;Table of Contents;6
5;List of Contributors;10
6;Preface;12
7;Contents of Other Volumes;14
8;Chapter 1. Advances in the Methodology of Quantitative Drug Design;22
8.1;I. How Should the Original Lead Be Used in the Design of Analogs?;23
8.2;A. BATCH SELECTION METHODS;24
8.3;B. STEP WISE METHODS;30
8.4;II. Which Physical Properties Should Be Related to Potency?;37
8.5;A. TRADITIONAL SUBSTITUENT CONSTANTS;37
8.6;B. NEW PARAMETERS FOR THE SIZE OF A SUBSTITUENT;38
8.7;C. THE EFFECTS OF SUBSTITUENTS ON THE CONFORMATION OF COMPOUNDS;41
8.8;D. MINIMAL STERIC DIFFERENCE (MSD) AND MINIMUM TOPOLOGICAL DIFFERENCE (MTD);42
8.9;E. MOLECULAR CONNECTIVITY;44
8.10;F. CONSIDERATION OF STEREOISOMERS;46
8.11;G. IMPROVED VALUES FOR ELECTRONIC EFFECTS;49
8.12;III. Calculation, Measurement, and Meaning of Partition Coefficients;49
8.13;A. CALCULATION OF PARTITION COEFFICIENTS;50
8.14;B. SIMULTANEOUS MEASUREMENTS OF pKa AND log P;52
8.15;C. CHROMATOGRAPHIC DETERMINATION OF HYDROPHOBICITY;53
8.16;D. Is THE OCTANOL-WATER log P A GOOD MEASURE OF HYDROPHOBICITY?;54
8.17;IV. Theoretical Compartment Models for the Relationship between Physical Properties and Biological Potency;57
8.18;A. SIMPLE LINEAR RELATIONSHIPS;60
8.19;B. NONLINEAR RELATIONSHIPS BETWEEN log P AND POTENCY;61
8.20;C. THE PROBLEM OF VARIABLE IONIZATION WITHIN THE SERIES;73
8.21;D. IMPLICATIONS FOR QSAR OF THE ABOVE MODELS;84
8.22;V. Mathematical Methods for the Analysis of QSAR;86
8.23;A. LINEAR REGRESSION ANALYSIS;86
8.24;B. NONLINEAR REGRESSION ANALYSIS;86
8.25;C. DISCRIMINANT ANALYSIS;86
8.26;D. OTHER STATISTICAL METHODS;88
8.27;VI. Overview;89
8.28;References;89
9;Chapter 2. The Application of Pattern Recognition to Drug Design;94
9.1;I. Introduction;94
9.2;II. Pattern Recognition : Philosophy and Methodology;96
9.3;A. BACKGROUND;96
9.4;B. PREPROCESSING;99
9.5;C. DISPLAY;100
9.6;D. SUPERVISED LEARNING;101
9.7;E. UNSUPERVISED LEARNING;103
9.8;F. INFORMATION FEEDBACK;104
9.9;III. Pattern Recognition Applications;105
9.10;IV. Conclusions;147
9.11;A. DATA SET SELECTION;147
9.12;B. FEATURE GENERATION;148
9.13;C. PREPROCESSING;149
9.14;D. CLASSIFICATION;150
9.15;E. DISPLAY/INFORMATION FEEDBACK;150
9.16;References;150
10;Chapter 3. The Design of Controlled Drug Delivery Systems;154
10.1;I. Introduction;155
10.2;II. Therapeutic Systems for Controlled Drug Delivery;156
10.3;A. COMPONENTS;156
10.4;B. BASIS FOR DEVELOPMENT;157
10.5;III. Two Therapeutic Systems for Clinical Use;158
10.6;A. RATIONALE FOR CONTROLLED DELIVERY;158
10.7;B. DEVELOPMENT OF THE OROS® SYSTEM;160
10.8;C. DEVELOPMENT OF THE TRANSDERMAL THERAPEUTIC SYSTEM;166
10.9;IV. The ALZET® Osmotic Minipump for Animal Studies;175
10.10;A. ANALYSIS OF LITERATURE ON ANTICANCER DRUG STUDIES;175
10.11;B. ESSENTIAL FEATURES OF MINIPUMP DESIGN AND USE;178
10.12;C. DETAILED DESIGN SPECIFICATIONS;181
10.13;D. PERFORMANCE OF OSMOTIC MINIPUMP;184
10.14;V. Conclusions;186
10.15;ACKNOWLEDGMENTS;186
10.16;References;186
11;Chapter 4. Receptor Binding as a Tool in the Development of New Bioactive Steroids;190
11.1;I. Introduction;191
11.2;II. Characterization of Steroid Hormone Receptors;193
11.3;A. PRIMARY LOCALIZATIONS;193
11.4;B. SPECIES AND TISSUE SIMILARITIES;194
11.5;III. Screening Methodology;196
11.6;A. CHOICE OF PREPARATION;196
11.7;B. CHOICE OF BINDING MEASUREMENT TECHNIQUE;197
11.8;C. CHOICE OF RADIOLIGAND;197
11.9;D. CHOICE OF COMPETITORS;203
11.10;IV. Screening Results;204
11.11;A. ESTRADIOL DERIVATIVES AND RELATED COMPOUNDS;204
11.12;B. PROGESTERONE DERIVATIVES AND RELATED COMPOUNDS;208
11.13;C. TESTOSTERONE DERIVATIVES AND RELATED COMPOUNDS;212
11.14;D. MlNERALOCORTICOIDS AND GLUCOCORTICOIDS;215
11.15;V. Conformation Studies;219
11.16;VI. Correlation between Binding Affinity and Biological Potency;221
11.17;A. BIOLOGICAL MODELS;221
11.18;B. DISTRIBUTION FACTORS;222
11.19;C. CORRELATIONS;223
11.20;D. BINDING AND ACTIVITY PROFILES;228
11.21;VIII. Conclusion;228
11.22;ACKNOWLEDGMENTS;229
11.23;References;230
12;Chapter 5. The Design of Synthetic Sweeteners;236
12.1;I. Introduction;236
12.2;A. HISTORICAL REVIEW OF SYNTHETIC DESIGN;238
12.3;B. MODERN RECEPTOR THEORY;242
12.4;C. THE NATURE OF THE ESSENTIAL GLUCOPHORE FOR SWEET TASTE;247
12.5;II. Design Concepts;253
12.6;A. INTRODUCTION;253
12.7;B. FUNCTIONALITY;256
12.8;C. CORRELATIONS OF SWEETNESS : SIZE, SHAPE, STEREOCHEMISTRY, AND POLARITY;270
12.9;D. LINEAR FREE ENERGY RELATIONSHIPS AND THEIR ROLE IN SWEETENER DESIGN;287
12.10;E. PREDICTION OF RECEPTOR SITE TOPOGRAPHY AS A TOOL IN SWEETENER DESIGN;297
12.11;F. SUMMARY;305
12.12;III. Current and Future Trends;306
12.13;A. MEASUREMENT OF SWEETNESS POTENCY;306
12.14;B. RECEPTOR MECHANISM, RECEPTOR ISOLATION, AND INTRACELLULAR EVENTS;317
12.15;C. A MODEL FOR THE SWEET TASTE RECEPTOR;320
12.16;D. SWEETNESS INHIBITORS;322
12.17;E. NON ABSORB ABLE SWEETENERS;323
12.18;ACKNOWLEDGMENTS;326
12.19;References;326
13;Chapter 6. The Prospective Assessment of Environmental Effects of Chemicals;332
13.1;I. Introduction;332
13.2;II. Identification of the Problem;334
13.3;III. Types of Tests to Be Carried Out;338
13.4;A. FACTORS DETERMINING THE ENVIRONMENTAL EFFECTS;342
13.5;B. SUBSTANCE-SPECIFIC DATA;343
13.6;C. TOXICITY;346
13.7;D. BIOSTIMULATION;351
13.8;E. BIOACCUMULATION;351
13.9;F. BIOLOGICAL BREAKDOWN AND TRANSFORMATION;354
13.10;G. MONITORING;357
13.11;IV. Choice of Test Organisms;359
13.12;V. Setup of the Test Program;366
13.13;VI. Areas for Further Research;368
13.14;A. REDUNDANCY OF TESTS;369
13.15;B. VALIDATION OF LABORATORY TESTS;369
13.16;C. REPRODUCIBILITY WITHIN AND BETWEEN LABORATORIES;371
13.17;VII. Conclusions;372
13.18;References;373
14;Chapter 7. Design of Selective Ion Binding Macrocyclic Compounds and Their Biological Applications;376
14.1;I. Introduction;377
14.2;A. RATIONALE FOR THE POSSIBLE USE OF MACROCYCLIC COMPOUNDS AS DRUGS;377
14.3;B. OBJECTIVES;379
14.4;II. Historical Perspective;379
14.5;A. IONOPHORES;379
14.6;B. PORPHYRIN ANALOGS;383
14.7;C. MACROCYCLIC POLYETHERS AND THEIR DERIVATIVES;383
14.8;III. Nomenclature and Physical Properties;384
14.9;A. NOMENCLATURE;384
14.10;B. PHYSICAL PROPERTIES;385
14.11;IV. Biological Applications;386
14.12;V. Synthesis;387
14.13;VI. Organic Reactions;388
14.14;A. ENHANCED SOLUBILITY OF SALTS IN ORGANIC SOLVENTS;389
14.15;B. REACTION OF INORGANIC SALTS IN NONAQUEOUS SOLVENTS;390
14.16;C. ELUCIDATION OF REACTION MECHANISMS;391
14.17;D. CATALYSIS;392
14.18;E. GUEST REACTIONS REMOTE FROM THE SITE OF ATTACHMENT TO THE HOST;392
14.19;VII. Structural Relationships;395
14.20;A. CYCLIC POLYETHERS AND THEIR DERIVATIVES;395
14.21;B. ANTIBIOTICS;398
14.22;C. CRYPTATES;399
14.23;D. NH4 +, Organic Cations, and Cl–;400
14.24;VIII. Cation Selectivities;400
14.25;A. METAL CATIONS;402
14.26;B. NH4 + AND ORGANIC CATIONS;409
14.27;IX. Potential of Macrocyclic Compounds as Drugs;412
14.28;A. SELECTIVE DETOXIFICATION OF METAL IONS;413
14.29;B. TRANSPORT OF CATIONS ACROSS BIOLOGICAL MEMBRANES;413
14.30;C. MACROCYCLIC ETHER TOXICITY;414
14.31;D. EFFECT OF STRUCTURAL MODIFICATIONS ON SPECIFIC DRUG DISTRIBUTION;414
14.32;ACKNOWLEDGMENTS;418
14.33;References;418
15;Index;422