Chirality in Drug Design and Development

✍ Scribed by Indra K. Reddy, Reza Mehvar

• Publisher: Marcel Dekker
• Year: 2004
• Tongue: English
• Leaves: 441
• Edition: 1
• Category: Library

✦ Synopsis

Covering every essential element in the development of chiral products, this reference provides a solid overview of the formulation, biopharmaceutical characteristics, and regulatory issues impacting the production of these pharmaceuticals—supporting researchers as they critically evaluate the pharmacodynamic, pharmacokinetic, and toxicological characteristics of specific enantiomers and chiral drug compounds.

✦ Table of Contents

CHIRALITY IN DRUG DESIGN AND DEVELOPMENT......Page 1
FOREWORD......Page 3
PREFACE......Page 7
CHAPTER 7: STEREOSPECIFIC PHARMACOKINETICS AND PHARMACODYNAMICS: CARDIOVASCULAR DRUGS......Page 9
CHAPTER 10: REGULATORY CONSIDERATIONS IN DRUG DEVELOPMENT OF STEREOISOMERS......Page 10
CONTRIBUTORS......Page 11
CONTENTS......Page 0
1. INTRODUCTION......Page 13
2. ENANTIOMERS, RACEMIC SPECIES (OR RACEMATES), AND DIASTEREOMERS......Page 14
4.1. NATURE OF RACEMATES......Page 15
4.2. THERMODYNAMIC STABILITY OF THE RACEMIC COMPOUND......Page 22
4.3. POLYMORPHISM AND PSEUDOPOLYMORPHISM OF CHIRAL DRUGS......Page 23
4.4. CRYSTAL STRUCTURES OF CHIRAL DRUGS......Page 29
4.5. CRYSTAL PROPERTIES OF ENANTIOMERS AND RACEMIC COMPOUNDS......Page 30
5.1. SOLUBILITY OF CHIRAL DRUGS......Page 31
5.2. STEREOSELECTIVE RELEASE OF CHIRAL DRUGS......Page 32
6. INFLUENCE OF STEREOISOMERIC IMPURITIES IN THE CRYSTALLIZATION MEDIUM ON THE PHYSICAL PROPERTIES OF CHIRAL DRUGS......Page 34
7. APPLICATION OF MOLECULAR MODELING IN PREDICTING THE PHYSICAL PROPERTIES OF CHIRAL DRUGS......Page 36
8. CONCLUDING REMARKS......Page 41
REFERENCES......Page 42
1. INTRODUCTION......Page 49
2. CHALLENGES AND REGULATORY PERSPECTIVES IN THE DEVELOPMENT OF FORMULATIONS CONTAINING CHIRAL DRUGS......Page 50
3. PROPERTIES AND CHARACTERIZATION OF CHIRAL EXCIPIENTS......Page 53
4.1. CELLULOSES......Page 59
4.2. CYCLODEXTRINS......Page 67
4.3. MOLECULARLY IMPRINTED POLYMERS......Page 71
4.4. MISCELLANEOUS......Page 72
REFERENCES......Page 73
1. INTRODUCTION......Page 78
2. SKIN STRUCTURE AND BARRIER FUNCTION......Page 79
3. STEREOSELECTIVE BINDING, METABOLISM, AND PHARMACODYNAMIC EFFECTS IN THE SKIN......Page 83
4.1. ENANTIOSELECTIVE SKIN PERMEATION......Page 87
4.2. THE MTMT CONCEPT......Page 92
5. EUTECTICS AND CHIRAL TERPENE ENHANCERS......Page 97
6. CONCLUSIONS......Page 103
REFERENCES......Page 105
1. INTRODUCTION......Page 111
2. DESIGN OF PRODRUGS......Page 112
4.1. UTILIZATION OF MONOSACCHARIDE TRANSPORTERS FOR DRUG ABSORPTION......Page 115
4.2. UTILIZATION OF OLIGOPEPTIDE TRANSPORTERS......Page 119
4.3. UTILIZATION OF BILE ACID TRANSPORTERS......Page 121
5. TARGETING DRUGS TO THE KIDNEY USING RENAL SPECIFIC TRANSPORTERS AND ENZYMES......Page 126
6.1. BIODEGRADATION OF AMINO ACID PRODRUGS BY AMINOPEPTIDASES......Page 127
6.2. ANTIBODY- AND GENE-DIRECTED ENZYME PRODRUG THERAPIES......Page 129
6.3. BIOCONVERSION OF ESTER-CONTAINING PRODRUGS BY CARBOXYLESTERASES......Page 131
6.4. STEREOSELECTIVE TRANSDERMAL TRANSPORT OF PRODRUGS......Page 137
7. CONCLUSIONS......Page 143
REFERENCES......Page 144
1. INTRODUCTION......Page 148
2. BIOLOGICAL DISCRIMINATION OF STEREOISOMERS......Page 149
2.1. STEREOCHEMICAL TERMINOLOGY AND PHARMACODYNAMIC ACTIVITY......Page 155
2.2. EUDISMIC RATIO AND ENANTIOMERIC PURITY......Page 157
3. PHARMACODYNAMIC COMPLEXITIES......Page 159
3.1. DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKING AGENTS......Page 161
3.2. KETAMINE......Page 163
3.3. DICHLOROPHENOXYACETIC ACID DIURETIC AGENTS......Page 164
3.4. SELECTIVE SEROTONIN REUPTAKE INHIBITORS......Page 165
4.1. ABSORPTION......Page 168
4.2. DISTRIBUTION......Page 169
4.3. METABOLISM......Page 170
4.4. RENAL EXCRETION......Page 175
4.5. PHARMACOKINETIC PARAMETERS......Page 178
5.1. B-LACTAM ANTIMICROBIAL AGENTS......Page 179
5.2. DESIGN OF B-ADRENOCEPTOR ANTAGONIST PRODRUGS......Page 180
6.1. THALIDOMIDE AND RELATED TERATOGENIC AGENTS......Page 181
6.3. MALE ANTIFERTILITY AGENTS......Page 183
7. CHIRAL SWITCHES......Page 184
8. CONCLUDING COMMENTS......Page 186
REFERENCES......Page 187
1. INTRODUCTION......Page 200
2.1. ANTIBIOTICS......Page 204
2.2. ANTIVIRALS......Page 205
2.3. ANTIMALARIALS......Page 214
2.4. ANTIHELMINTHIC DRUGS......Page 218
3. ORAL ANTICOAGULANTS......Page 219
3.1. STEREOSELECTIVE PHARMACOKINETICS/DYNAMICS OF ORAL ANTICOAGULANTS......Page 220
3.2. DRUG INTERACTIONS AFFECTING PHARMACOKINETICS/ DYNAMICS OF COUMARIN ANTICOAGULANTS......Page 225
PHARMACODYNAMICS......Page 227
PHARMACOKINETICS......Page 230
SPECIAL USE OF STEREOSELECTIVE PHARMACOKINETIC DATA OF B-AGONISTS......Page 234
5.1. ANTIPSYCHOTICS......Page 235
FLUOXETINE......Page 236
CITALOPRAM......Page 237
REBOXETINE......Page 238
TRANYLCYPROMINE......Page 239
TRIMIPRAMINE......Page 240
5.4. SEDATIVE/HYPNOTICS......Page 241
6.1. PARKINSONS DISEASE......Page 243
ETHOSUXIMIDE......Page 244
VIGABATRIN......Page 245
ANALOGS OF VALPROIC ACID......Page 246
7. ANALGESICS......Page 247
VOLATILE ANESTHETICS......Page 249
INJECTABLE ANESTHETICS......Page 250
8.2. LOCAL ANESTHETICS......Page 252
9. DRUGS AFFECTING MUSCLE FUNCTION......Page 254
10. DRUGS USED TO TREAT ALLERGIES......Page 255
11. DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISORDERS......Page 256
13. DRUGS OF ABUSE......Page 258
14.1. CYCLOPHOSPHAMIDE AND IFOSFAMIDE......Page 259
15. DRUGS USED TO TREAT CONNECTIVE TISSUE DISORDERS: THE NONSTEROIDAL ANTI-INFLAMMATORY DRUGS......Page 261
15.1. STEREOSELECTIVITY IN PLASMA CONCENTRATIONS OF NSAIDS......Page 262
DISTRIBUTION......Page 264
METABOLISM......Page 265
15.3. CLINICAL FACTORS AFFECTING PLASMA CONCENTRATIONS OF NSAIDS......Page 267
16. CONCLUSION......Page 268
REFERENCES......Page 269
2. BETA-ADRENERGIC ANTAGONISTS......Page 290
2.1. STEREOSELECTIVITY IN PHARMACOLOGICAL ACTION......Page 291
DISTRIBUTION......Page 292
ELIMINATION......Page 296
AGE AND GENDER......Page 301
ENANTIOMER–ENANTIOMER OR DRUG–DRUG INTERACTIONS......Page 305
RATE OF DRUG INPUT......Page 306
GENETIC FACTORS......Page 307
CONGESTIVE HEART FAILURE......Page 309
4. THE 1,4-DIHYDROPYRIDINE CALCIUM CHANNEL ANTAGONISTS......Page 310
4.1. STEREOSELECTIVITY IN PHARMACOLOGICAL ACTIONS......Page 311
4.2. STEREOSELECTIVITY IN PHARMACOKINETICS......Page 312
5.1. STEREOSELECTIVITY IN PHARMACOLOGIC ACTION......Page 316
DISTRIBUTION......Page 319
METABOLISM......Page 321
RENAL EXCRETION......Page 324
DISOPYRAMIDE......Page 327
ENCAINIDE......Page 329
MEXILETINE......Page 330
PROPAFENONE......Page 333
TOCAINIDE......Page 336
VERAPAMIL......Page 338
6.1. PRENYLAMINE......Page 344
6.3. GALLOPAMIL......Page 345
7. CONCLUSION......Page 346
REFERENCES......Page 347
1. INTRODUCTION......Page 360
2.1. NSAIDS: 2-ARYLPROPIONIC ACIDS......Page 361
2.2. MECHANISMS......Page 362
3. LIPIDS......Page 364
4. BIDIRECTIONAL R TO S AND S TO R INVERSION......Page 366
5. SPECIES DIFFERENCES IN INVERSION......Page 368
6. SITES OF BIOINVERSION......Page 369
7. KETOROLAC: BIOINVERSION / RACEMIZATION......Page 370
8. INVERSION BY OPPOSING METABOLIC PROCESSES: OXIDOREDUCTION......Page 371
9. A-AMINO ACIDS......Page 379
11. STIRIPENTOL: OXIODOREDUCTION/CONJUGATION/ RACEMIZATION?......Page 383
12. THERAPEUTIC IMPLICATIONS OF BIOINVERSION......Page 384
REFERENCES......Page 389
1. INTRODUCTION......Page 402
2. ENANTIOMER INTERCONVERSION......Page 404
3. STEREOSELECTIVE FIRST-PASS METABOLISM......Page 405
4. DEMONSTRATION OF ORAL INPUT RELATED SATURABLE ENANTIOSELECTIVE FIRST-PASS METABOLISM......Page 409
6. APPRAISALS OF VARIOUS PROPOSALS ON THE USE OF STEREOSELECTIVE ASSAYS IN BIOEQUIVALENCY STUDIES......Page 410
7.1. CATEGORY I DRUGS......Page 413
7.2. CATEGORY II DRUGS......Page 415
7.3. CATEGORY II DRUG WITH RACEMIC INVERSION......Page 416
7.4. CATEGORY III DRUGS......Page 417
9. CONCLUSIONS......Page 420
REFERENCES......Page 421
1.1. DRUG DEVELOPMENT AND THE REGULATORY PROCESS......Page 428
1.2. REGULATORY GUIDANCE......Page 429
3.1. PHARMACOLOGY......Page 431
4. DEVELOPING RACEMATES OR SINGLE ENANTIOMERS......Page 432
5.1. DEVELOPING AN ISOMER......Page 434
5.2. BIOPHARMACEUTICS......Page 435
5.3. CLINICAL PHARMACOLOGY......Page 436
6. EXCLUSIVITY......Page 437
7. CONCLUSIONS......Page 439
REFERENCES......Page 440