Drug Design (eBook)

Front Cover 1
Drug Design 4
Copyright Page 5
Table of Contents 6
List of Contributors 12
Preface 14
Introduction 16
Contents of Other Volumes 18
Chapter 1. Modulation of Pharmacokinetics by Molecular Manipulation 22
I. Introduction 23
II. The Significance of the Chemical Structure of Bioactive Compounds with Regard to the Various Processes Involved in Pharmacokinetics 24
III. Dissection of the Drug Molecule in Biofunctional Moieties 28
IV. Modulation of the Distribution of Pharmaca over the Various Compartments in Individual and Environmental Pharmacokinetics by Molecular Manipulation 33
V. Modulation of the Time–Concentration Relationship in the Distribution of Drugs by Molecular Manipulation 90
VI. Summary 138
REFERENCES 138
Chapter 2. Factors in the Design of Reversible and Irreversible Enzyme Inhibitors 150
I. Introduction 150
II. Mechanism of Action of Selected Drugs 154
III. Factors Involved in the Reversible Inhibition of Selected Enzymes 159
IV. Irreversible Inhibition of Selected Enzymes 167
V. Kinetics of Irreversible Enzyme Inactivation 170
VI. Tissue-Specific Irreversible Enzyme Inhibitors 176
VII. Summary 179
ACKNOWLEDGMENT 180
REFERENCES 180
Chapter 3. The Design of Organophosphate and Carbamate Inhibitors of Cholinesterases 182
I. Introduction 183
II. The Structure of the Active Zone of Cholinesterases 185
III. Design of Organophosphates 201
IV. Design of Carbamates 217
V. Future Approaches to Design of Anticholinesterases 227
REFERENCES 229
Chapter 4. The Design of Reactivators for Irreversibly Blocked Acetylcholinesterase 234
Text 234
REFERENCES 248
Chapter 5. Inhibition of Protein Biosynthesis: Its Significance in Drug Design 252
I. Introduction 252
II. Protein Biosynthesis 253
III. Inhibitors of Protein Synthesis 255
IV. Design of Antibacterial Agents 256
V. Design of Amebicidal Agents 257
VI. Design of Antitumor Agents 266
VII. Design of Emetic Agents 267
VIII. Design of Antiviral Agents 268
IX. Conclusions 268
ACKNOWLEDGMENT 268
REFERENCES 269
Chapter 6. Enzymes and Their Synthesis as a Target for Antibiotic Action 272
I. Introduction 272
II. Competitive Inhibitors of Enzymes 273
III. Irreversible Inhibitors or Enzymes as Antibacterial Agents 276
IV. Conclusion 280
REFERENCES 281
Chapter 7. The Rational Design of Antiviral Agents 282
I. Introduction 282
II. Approaches to the Design of Antiviral Agents 287
III. Conclusions 293
ACKNOWLEDGMENTS 293
REFERENCES 294
Chapter 8. Design of Penicillins 298
I. Introduction 298
II. Effect of Penicillins on Bacteria 303
III. Behavior of Penicillins in Vivo 321
IV. Derivatives Which Liberate Penicillins in Vivo 334
V. Concluding Remarks 335
ACKNOWLEDGMENT 336
REFERENCES 336
Chapter 9. The Design of Peptide Hormone Analogs 340
I. Introduction 340
II. Structural Aspects of Design 349
III. Biological Aspects and Practical Aims of Design 391
IV. Conclusions 422
ACKNOWLEDGMENTS 422
REFERENCES 422
Chapter 10. Recent Advances in the Design of Diuretics 442
I. Introduction 442
II. Mono- and Bicyclic Nitrogen Heterocycles 443
III. Sulfonamides and Disulfonamides 449
IV. a,ß-Unsaturated Ketone Derivatives 452
V. Miscellaneous Group 453
REFERENCES 455
Chapter 11. Design of Biologically Active Steroids 458
I. Introduction 458
II. Chemical Exploration and Pharmacological Screening 459
III. The Biological Study of the Cause of Disease 470
REFERENCES 472
Chapter 12. Rational Elements in the Development of Superior Neuromuscular Blocking Agents 474
I. Introduction 475
II. Grosser Morphological Features Influencing the Response to Neuromuscular Blocking Agents 477
III. The Anatomy and Physiology of the Neuromuscular Junction 479
IV. Mechanisms of Neuromuscular Blockade 503
V. Clinically Desirable Features in a Neuromuscular Blocking Agent 514
VI. Relationships between Chemical Constitution and Neuromuscular Blocking Activity 516
VII. Rational Applications of Structure–Action Relationships to the Synthesis of New Neuromuscular Blocking Agents 520
VIII· Conclusion 534
REFERENCES 535
Chapter 13. The Design of Tumor-Inhibitory Alkylating Drugs 552
I. Introduction 553
II. Types of Alkylating Groups 554
III. Sites of Reaction and Correlation with Biological Effects 557
IV. General Structural Considerations 558
V. Number of Reactive Centers 567
VI. Naturally Occurring Compounds and Analogs as Carriers of Alkylating Groups 570
VII. Dual Antagonists 578
VIII. Alkylating Agents Capable of Being Activated or Potentiated 579
IX. The Application of pH Differences 584
X. Compounds Designed for Intraarterial Infusion 586
XI. Conclusion 586
ACKNOWLEDGMENT 587
REFERENCES 587
Author Index 594
Subject Index 638