Drug Design (eBook)

Front Cover 1
Drug Design 4
Copyright Page 5
Table of Contents 6
List of Contributors 10
Preface 12
Contents of Other Volumes 14
Chapter 1. Advances in the Methodology of Quantitative Drug Design 22
I. How Should the Original Lead Be Used in the Design of Analogs? 23
A. BATCH SELECTION METHODS 24
B. STEP WISE METHODS 30
II. Which Physical Properties Should Be Related to Potency? 37
A. TRADITIONAL SUBSTITUENT CONSTANTS 37
B. NEW PARAMETERS FOR THE SIZE OF A SUBSTITUENT 38
C. THE EFFECTS OF SUBSTITUENTS ON THE CONFORMATION OF COMPOUNDS 41
D. MINIMAL STERIC DIFFERENCE (MSD) AND MINIMUM TOPOLOGICAL DIFFERENCE (MTD) 42
E. MOLECULAR CONNECTIVITY 44
F. CONSIDERATION OF STEREOISOMERS 46
G. IMPROVED VALUES FOR ELECTRONIC EFFECTS 49
III. Calculation, Measurement, and Meaning of Partition Coefficients 49
A. CALCULATION OF PARTITION COEFFICIENTS 50
B. SIMULTANEOUS MEASUREMENTS OF pKa AND log P 52
C. CHROMATOGRAPHIC DETERMINATION OF HYDROPHOBICITY 53
D. Is THE OCTANOL-WATER log P A GOOD MEASURE OF HYDROPHOBICITY? 54
IV. Theoretical Compartment Models for the Relationship between Physical Properties and Biological Potency 57
A. SIMPLE LINEAR RELATIONSHIPS 60
B. NONLINEAR RELATIONSHIPS BETWEEN log P AND POTENCY 61
C. THE PROBLEM OF VARIABLE IONIZATION WITHIN THE SERIES 73
D. IMPLICATIONS FOR QSAR OF THE ABOVE MODELS 84
V. Mathematical Methods for the Analysis of QSAR 86
A. LINEAR REGRESSION ANALYSIS 86
B. NONLINEAR REGRESSION ANALYSIS 86
C. DISCRIMINANT ANALYSIS 86
D. OTHER STATISTICAL METHODS 88
VI. Overview 89
References 89
Chapter 2. The Application of Pattern Recognition to Drug Design 94
I. Introduction 94
II. Pattern Recognition : Philosophy and Methodology 96
A. BACKGROUND 96
B. PREPROCESSING 99
C. DISPLAY 100
D. SUPERVISED LEARNING 101
E. UNSUPERVISED LEARNING 103
F. INFORMATION FEEDBACK 104
III. Pattern Recognition Applications 105
IV. Conclusions 147
A. DATA SET SELECTION 147
B. FEATURE GENERATION 148
C. PREPROCESSING 149
D. CLASSIFICATION 150
E. DISPLAY/INFORMATION FEEDBACK 150
References 150
Chapter 3. The Design of Controlled Drug Delivery Systems 154
I. Introduction 155
II. Therapeutic Systems for Controlled Drug Delivery 156
A. COMPONENTS 156
B. BASIS FOR DEVELOPMENT 157
III. Two Therapeutic Systems for Clinical Use 158
A. RATIONALE FOR CONTROLLED DELIVERY 158
B. DEVELOPMENT OF THE OROS® SYSTEM 160
C. DEVELOPMENT OF THE TRANSDERMAL THERAPEUTIC SYSTEM 166
IV. The ALZET® Osmotic Minipump for Animal Studies 175
A. ANALYSIS OF LITERATURE ON ANTICANCER DRUG STUDIES 175
B. ESSENTIAL FEATURES OF MINIPUMP DESIGN AND USE 178
C. DETAILED DESIGN SPECIFICATIONS 181
D. PERFORMANCE OF OSMOTIC MINIPUMP 184
V. Conclusions 186
ACKNOWLEDGMENTS 186
References 186
Chapter 4. Receptor Binding as a Tool in the Development of New Bioactive Steroids 190
I. Introduction 191
II. Characterization of Steroid Hormone Receptors 193
A. PRIMARY LOCALIZATIONS 193
B. SPECIES AND TISSUE SIMILARITIES 194
III. Screening Methodology 196
A. CHOICE OF PREPARATION 196
B. CHOICE OF BINDING MEASUREMENT TECHNIQUE 197
C. CHOICE OF RADIOLIGAND 197
D. CHOICE OF COMPETITORS 203
IV. Screening Results 204
A. ESTRADIOL DERIVATIVES AND RELATED COMPOUNDS 204
B. PROGESTERONE DERIVATIVES AND RELATED COMPOUNDS 208
C. TESTOSTERONE DERIVATIVES AND RELATED COMPOUNDS 212
D. MlNERALOCORTICOIDS AND GLUCOCORTICOIDS 215
V. Conformation Studies 219
VI. Correlation between Binding Affinity and Biological Potency 221
A. BIOLOGICAL MODELS 221
B. DISTRIBUTION FACTORS 222
C. CORRELATIONS 223
D. BINDING AND ACTIVITY PROFILES 228
VIII. Conclusion 228
ACKNOWLEDGMENTS 229
References 230
Chapter 5. The Design of Synthetic Sweeteners 236
I. Introduction 236
A. HISTORICAL REVIEW OF SYNTHETIC DESIGN 238
B. MODERN RECEPTOR THEORY 242
C. THE NATURE OF THE ESSENTIAL GLUCOPHORE FOR SWEET TASTE 247
II. Design Concepts 253
A. INTRODUCTION 253
B. FUNCTIONALITY 256
C. CORRELATIONS OF SWEETNESS : SIZE, SHAPE, STEREOCHEMISTRY, AND POLARITY 270
D. LINEAR FREE ENERGY RELATIONSHIPS AND THEIR ROLE IN SWEETENER DESIGN 287
E. PREDICTION OF RECEPTOR SITE TOPOGRAPHY AS A TOOL IN SWEETENER DESIGN 297
F. SUMMARY 305
III. Current and Future Trends 306
A. MEASUREMENT OF SWEETNESS POTENCY 306
B. RECEPTOR MECHANISM, RECEPTOR ISOLATION, AND INTRACELLULAR EVENTS 317
C. A MODEL FOR THE SWEET TASTE RECEPTOR 320
D. SWEETNESS INHIBITORS 322
E. NON ABSORB ABLE SWEETENERS 323
ACKNOWLEDGMENTS 326
References 326
Chapter 6. The Prospective Assessment of Environmental Effects of Chemicals 332
I. Introduction 332
II. Identification of the Problem 334
III. Types of Tests to Be Carried Out 338
A. FACTORS DETERMINING THE ENVIRONMENTAL EFFECTS 342
B. SUBSTANCE-SPECIFIC DATA 343
C. TOXICITY 346
D. BIOSTIMULATION 351
E. BIOACCUMULATION 351
F. BIOLOGICAL BREAKDOWN AND TRANSFORMATION 354
G. MONITORING 357
IV. Choice of Test Organisms 359
V. Setup of the Test Program 366
VI. Areas for Further Research 368
A. REDUNDANCY OF TESTS 369
B. VALIDATION OF LABORATORY TESTS 369
C. REPRODUCIBILITY WITHIN AND BETWEEN LABORATORIES 371
VII. Conclusions 372
References 373
Chapter 7. Design of Selective Ion Binding Macrocyclic Compounds and Their Biological Applications 376
I. Introduction 377
A. RATIONALE FOR THE POSSIBLE USE OF MACROCYCLIC COMPOUNDS AS DRUGS 377
B. OBJECTIVES 379
II. Historical Perspective 379
A. IONOPHORES 379
B. PORPHYRIN ANALOGS 383
C. MACROCYCLIC POLYETHERS AND THEIR DERIVATIVES 383
III. Nomenclature and Physical Properties 384
A. NOMENCLATURE 384
B. PHYSICAL PROPERTIES 385
IV. Biological Applications 386
V. Synthesis 387
VI. Organic Reactions 388
A. ENHANCED SOLUBILITY OF SALTS IN ORGANIC SOLVENTS 389
B. REACTION OF INORGANIC SALTS IN NONAQUEOUS SOLVENTS 390
C. ELUCIDATION OF REACTION MECHANISMS 391
D. CATALYSIS 392
E. GUEST REACTIONS REMOTE FROM THE SITE OF ATTACHMENT TO THE HOST 392
VII. Structural Relationships 395
A. CYCLIC POLYETHERS AND THEIR DERIVATIVES 395
B. ANTIBIOTICS 398
C. CRYPTATES 399
D. NH4 +, Organic Cations, and Cl– 400
VIII. Cation Selectivities 400
A. METAL CATIONS 402
B. NH4 + AND ORGANIC CATIONS 409
IX. Potential of Macrocyclic Compounds as Drugs 412
A. SELECTIVE DETOXIFICATION OF METAL IONS 413
B. TRANSPORT OF CATIONS ACROSS BIOLOGICAL MEMBRANES 413
C. MACROCYCLIC ETHER TOXICITY 414
D. EFFECT OF STRUCTURAL MODIFICATIONS ON SPECIFIC DRUG DISTRIBUTION 414
ACKNOWLEDGMENTS 418
References 418
Index 422