Prodrugs and targeted delivery : towards better ADME properties
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Bibliographic Information
Prodrugs and targeted delivery : towards better ADME properties
（Methods and principles in medicinal chemistry / edited by R. Mannhold ... [et al.], v. 47）
Wiley-VCH, c2011
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Includes bibliographical references and index
Description and Table of Contents
Description
This topical reference and handbook addresses the chemistry, pharmacology, toxicology and the patentability of prodrugs, perfectly mirroring the integrated approach prevalent in today's drug design. It summarizes current experiences and strategies for the rational design of prodrugs, beginning at the early stages of the development process, as well as discussing organ- and site-selective prodrugs.
Every company employing medicinal chemists will be interested in this practice-oriented overview of a key strategy in modern drug discovery and development.
Table of Contents
List of Contributors XVII
Preface XXI
A Personal Foreword XXIII
Part One Prodrug Design and Intellectual Property 1
1 Prodrug Strategies in Drug Design 3
Jarkko Rautio
1.1 Prodrug Concept 3
1.2 Basics of Prodrug Design 4
1.3 Rationale for Prodrug Design 5
1.3.1 Overcoming Formulation and Administration Problems 6
1.3.2 Overcoming Absorption Barriers 8
1.3.3 Overcoming Distribution Problems 9
1.3.4 Overcoming Metabolism and Excretion Problems 10
1.3.5 Overcoming Toxicity Problems 10
1.3.6 Life Cycle Management 13
1.4 History of Prodrug Design 14
1.5 Recently Marketed Prodrugs 17
1.5.1 Prodrug Prevalence 17
1.5.2 Recent Prodrug Approvals 17
1.6 Concluding Remarks 25
References 26
2 The Molecular Design of Prodrugs by Functional Group 31
Victor R. Guarino
2.1 Introduction 31
2.2 The Prodrug Concept and Basics of Design 32
2.3 Common Functional Group Approaches in Prodrug Design 34
2.3.1 Aliphatic and Aromatic Alcohols 34
2.3.1.1 Phosphate Monoesters 35
2.3.1.2 Simple Acyl Esters 37
2.3.1.3 Amino Acid Esters 38
2.3.1.4 Other Ester-Based Approaches 39
2.3.2 Carboxylic Acids 40
2.3.2.1 Alkyl Esters 41
2.3.2.2 Aminoalkyl Esters 42
2.3.2.3 Spacer Groups to Alleviate Steric Hindrance 42
2.3.3 Imides, Amides, and Other NH Acids 43
2.3.3.1 Imide-Type NH Acids 44
2.3.3.2 Amide-Type NH Acids 44
2.3.3.3 Sulfonamide NH Acids 48
2.3.4 Phosphates, Phosphonates, and Phosphinates 49
2.3.4.1 Simple Alkyl and Aryl Esters 49
2.3.4.2 Acyloxyalkyl and Alkoxycarbonyloxyalkyl Esters 50
2.3.4.3 Aryl Phospho(n/r)amidates and Phospho(n/r)diamides 51
2.3.4.4 HepDirect Technology 53
2.3.5 Amines and Benzamidines 53
2.3.5.1 N-Acyloxyalkoxycarbonyl Prodrugs 54
2.3.5.2 N-Mannich Bases 55
2.3.5.3 N-Acyloxyalkyl and N-Phosphoryloxyalkyl Prodrugs of Tertiary Amines 55
2.3.5.4 N-Hydroxy and Other Modifications for Benzamidines 56
2.4 Conclusions 56
References 57
3 Intellectual Property Primer on Pharmaceutical Patents with a Special Emphasis on Prodrugs and Metabolites 61
Eyal H. Barash
3.1 Introduction 61
3.2 Patents and FDA Approval Process 61
3.3 Obtaining a Patent 65
3.3.1 Utility 66
3.3.2 Novelty 67
3.3.3 Nonobviousness 71
3.4 Conclusion 78
Part Two Prodrugs Addressing ADMET Issues 79
4 Increasing Lipophilicity for Oral Drug Delivery 81
Majid Y. Moridani
4.1 Introduction 81
4.2 pKa, Degree of Ionization, Partition Coefficient, and Distribution Coefficient 81
4.3 Prodrug Strategies to Enhance Lipid Solubility 85
4.4 Prodrug Examples for Antibiotics 87
4.4.1 Bacampicillin 87
4.4.2 Carindacillin 88
4.4.3 Cefditoren Pivoxil 89
4.4.4 Cefuroxime Axetil 90
4.4.5 Cefpodoxime Proxetil 91
4.5 Antiviral Related Prodrugs 92
4.5.1 Oseltamivir 92
4.5.2 Famciclovir 92
4.5.3 Adefovir Dipivoxil 93
4.5.4 Tenofovir Disoproxil 94
4.6 Cardiovascular Related Prodrugs 95
4.6.1 Enalapril 95
4.6.2 Fosinopril 96
4.6.3 Olmesartan Medoxomil 97
4.7 Lipophilic Prodrugs of Benzamidine Drugs 98
4.7.1 Ximelagatran 98
4.7.2 Dabigatran Etexilate 99
4.8 Miscellaneous Examples 100
4.8.1 Capecitabine 100
4.8.2 Mycophenolate Mofetil 101
4.8.3 Misoprostol 102
4.8.4 Additional Examples 102
4.9 Summary and Conclusion 104
References 106
5 Modulating Solubility Through Prodrugs for Oral and IV Drug Delivery 111
Victor R. Guarino
5.1 Introduction 111
5.2 Basics of Solubility and Oral/IV Drug Delivery 112
5.2.1 Some Basic Fundamentals of Solubility 112
5.2.2 Some General Comments on IV Drug Delivery 114
5.2.3 Some General Comments on Oral Drug Delivery 116
5.3 Prodrug Applications for Enhanced Aqueous Solubility 117
5.3.1 Prodrug Concept 117
5.3.2 Examples of Prodrugs to Enhance Aqueous Solubility for IV Administration 118
5.3.2.1 Fosphenytoin 118
5.3.2.2 Fospropofol 119
5.3.2.3 Parecoxib 120
5.3.2.4 Irinotecan 120
5.3.3 Prodrugs to Enhance Aqueous Solubility for Oral Administration 121
5.3.3.1 Fosamprenavir 121
5.3.3.2 Valganciclovir 122
5.4 Challenges with Solubilizing Prodrugs of Insoluble Drugs 123
5.4.1 Challenges with Solubilizing Prodrug Strategies for IV Administration 123
5.4.2 Challenges with Solubilizing Prodrug Strategies for Oral Administration 124
5.5 Additional Applications of Prodrugs for Modulating Solubility 125
5.5.1 Alleviating pH-Dependent Oral Bioavailability of Weakly Basic Drugs 126
5.5.2 Aligning pH-Solubility and pH-Stability Relationships for IV Products 126
5.5.3 Modulating Solubility in Negative Direction 127
5.6 Parallel Exploration of Analogues and Prodrugs in Drug Discovery (Commentary) 128
5.7 Conclusions 129
References 129
6 Prodrugs Designed to Target Transporters for Oral Drug Delivery 133
Mark S. Warren and Jarkko Rautio
6.1 Introduction 133
6.2 Serendipity: An Actively Transported Prodrug 133
6.3 Requirements for Actively Transported Prodrugs 135
6.4 Peptide Transporters: PEPT1 and PEPT2 135
6.5 Monocarboxylate Transporters 140
6.6 Bile Acid Transporters 143
6.7 Conclusions 147
References 147
7 Topical and Transdermal Delivery Using Prodrugs: Mechanism of Enhancement 153
Kenneth Sloan, Scott C. Wasdo, and Susruta Majumdar
7.1 Introduction 153
7.2 Arrangement of Water in the Stratum Corneum 155
7.3 A New Model for Diffusion Through the Stratum Corneum: The Biphasic Solubility Model 156
7.4 Equations for Quantifying Effects of Solubility on Diffusion Through the Stratum Corneum 158
7.4.1 The Roberts-Sloan Equation When the Vehicle is Water 159
7.4.2 The Roberts-Sloan Equation When the Vehicle is a Lipid 160
7.4.3 The Series/Parallel Equation When the Vehicle is a Lipid 161
7.5 Design of Prodrugs for Topical and Transdermal Delivery Based on the Biphasic Solubility Model 162
7.5.1 5-Fluorouracil Prodrugs 164
7.5.1.1 N-Acyl 5-FU Prodrugs 165
7.5.1.2 N-Soft Alkyl 5-FU Prodrugs 166
7.5.2 Acetaminophen (APAP) Prodrugs 167
7.5.2.1 O-Acyl APAP Prodrugs 168
7.5.2.2 O-Soft Alkyl APAP Prodrugs 170
7.5.3 S-Soft Alkyl Prodrugs of 6-Mercaptopurine 170
7.5.3.1 Effect of Vehicles on Topical and Transdermal Delivery 171
7.6 Comparison of Human and Mouse Skin Experiments 172
7.7 Summary 174
References 175
8 Ocular Delivery Using Prodrugs 181
Deep Kwatra, Ravi Vaishya, Ripal Gaudana, Jwala Jwala, and Ashim K. Mitra
8.1 Introduction 181
8.2 Criteria for an Ideal Ophthalmic Prodrug 181
8.3 Anatomy and Physiology of the Eye 182
8.3.1 Anterior Chamber 183
8.3.2 Posterior Chamber 183
8.4 Barriers to Ocular Drug Delivery 184
8.4.1 Tear Film 184
8.4.2 Corneal Epithelium 184
8.4.3 Aqueous Humor and BAB 184
8.4.4 Conjunctiva 184
8.4.5 Blood-Retinal Barrier 185
8.5 Influx and Efflux Transporters on the Eye 185
8.6 Transporter-Targeted Prodrug Approach 186
8.6.1 Acyclovir 186
8.6.2 Ganciclovir 188
8.6.3 Quinidine 188
8.7 Drug Disposition in Ocular Delivery 189
8.8 Effect of Physiochemical Factors on Drug Disposition in Eye 190
8.9 Prodrug Strategy to Improve Ocular Bioavailability (Nontransporter-Targeted Approach) 192
8.9.1 Epinephrine 192
8.9.2 Phenylephrine 192
8.9.3 Pilocarpine 193
8.9.4 Timolol 195
8.9.5 Prostaglandin F2a 197
8.10 Recent Patents and Marketed Ocular Prodrugs 198
8.11 Novel Formulation Approaches for Sustained Delivery of Prodrugs 201
8.12 Conclusion 201
References 202
9 Reducing Presystemic Drug Metabolism 207
Majid Y. Moridani
9.1 Introduction 207
9.2 Presystemic Metabolic Barriers 209
9.2.1 Esterases 209
9.2.2 Cytochrome P450 Enzymes 212
9.2.3 Phase II Drug Metabolizing Enzymes 214
9.2.4 Peptidases 215
9.2.5 Other Oxidative Metabolizing Enzymes 216
9.3 Prodrug Approaches to Reduce Presystemic Drug Metabolism 217
9.4 Targeting Colon 220
9.5 Targeting Lymphatic Route 221
9.6 Conclusion 225
References 226
10 Enzyme-Activated Prodrug Strategies for Site-Selective Drug Delivery 231
Krista Laine and Kristiina Huttunen
10.1 Introduction 231
10.2 General Requirements for Enzyme-Activated Targeted Prodrug Strategy 232
10.3 Examples of Targeted Prodrug Strategies 232
10.3.1 Tumor-Selective Prodrugs 232
10.3.1.1 Prodrugs Activated by Hypoxia-Associated Reductive Enzymes 233
10.3.1.2 Prodrugs Activated by Glutathione S-Transferase 236
10.3.1.3 Prodrugs Activated by Thymidine Phosphorylase 237
10.3.2 Organ-Selective Prodrugs 239
10.3.2.1 Liver-Targeted Prodrugs 239
10.3.2.2 Kidney-Targeted Prodrugs 242
10.3.2.3 Colon-Targeted Prodrugs 243
10.3.3 Virus-Selective Prodrugs 244
10.4 Summary 245
References 246
11 Prodrug Approaches for Central Nervous System Delivery 253
Quentin R. Smith and Paul R. Lockman
11.1 Blood-Brain Barrier in CNS Drug Development 253
11.2 Prodrug Strategies 255
11.3 Prodrug Strategies Based Upon BBB Nutrient Transporters 257
11.4 Prodrug Strategies Based Upon BBB Receptors 263
11.5 CNS Prodrug Summary 264
References 266
12 Directed Enzyme Prodrug Therapies 271
Dan Niculescu-Duvaz, Gabriel Negoita-Giras, Ion Niculescu-Duvaz, Douglas Hedley, and Caroline J. Springer
12.1 Introduction 271
12.2 Theoretical Background of DEPT 271
12.2.1 ADEPT and Other Enzyme-Conjugates Approaches 272
12.2.2 LIDEPT 273
12.2.3 GDEPT and Other Gene Delivery Approaches 273
12.2.4 BDEPT 275
12.3 Comparison of ADEPT and GDEPT 275
12.4 Enzymes in ADEPT and GDEPT 278
12.5 Design of Prodrugs 282
12.5.1 Mechanisms of Prodrug Activation 282
12.5.1.1 Electronic Switch 282
12.5.1.2 Cell Exclusion 285
12.5.1.3 Blockage of the Pharmacophore 285
12.5.1.4 Conversion to Substrate for Endogenous Enzymes 287
12.5.1.5 Formation of a Reactive Moiety 287
12.5.1.6 Formation of a Second Interactive Group 288
12.5.2 Enzymatic Reactions Activating the Prodrug. The Trigger 288
12.5.2.1 Reactions Catalyzed by Hydrolases: Hydrolytic Cleavage 289
12.5.2.2 Activation by Nucleotide Phosphorylation 290
12.5.2.3 Activation by Reductases 290
12.5.2.4 Activation by Oxidases 291
12.5.2.5 (Deoxy)Ribosyl Transfer 291
12.5.3 The Linker. Self-Immolative Prodrugs 292
12.5.3.1 Self-Immolative Prodrugs Fragmenting by Elimination 293
12.5.3.2 Linker-Drug Connection 293
12.5.3.3 Self-Immolative Prodrugs Fragmenting Following Cyclization 296
12.6 Strategies Used for the Improvement of DEPT Systems 296
12.6.1 Improvement of the Prodrug 296
12.6.1.1 Cytotoxicity Differential 297
12.6.1.2 Stability of Prodrugs 298
12.6.1.3 Cytotoxicity and Mechanism of Action of the Released Drug 299
12.6.1.4 Stability of the Released Drug 299
12.6.1.5 Resistance (Prodrug Related) 300
12.6.1.6 Kinetics of Activation 300
12.6.1.7 Physicochemical Properties 302
12.6.1.8 Pharmacokinetics 303
12.6.1.9 Specificity of Enzyme Activation 304
12.6.2 Improving the Enzymes 304
12.6.3 The Multigene Approach 305
12.6.4 Enhancing the Immune Response 307
12.7 Biological Data for ADEPT and GDEPT 307
12.7.1 Bacteria 308
12.7.2 Viruses 308
12.7.3 Adenoviral Vectors 308
12.7.4 Pox Viral Vectors 309
12.7.5 Adeno-Associated Viral Vectors 309
12.7.6 Retroviral Vectors 309
12.7.7 Lentiviral Vectors 310
12.7.8 Measles Viral Vectors 310
12.7.9 Herpes Simplex Viral Vectors 311
12.7.10 Neural Stem Cells/Progenitor Cells 311
12.7.11 Liposomes 311
12.7.12 ADEPT Vectors 312
12.7.13 Vectors for Prodrugs 312
12.7.14 Clinical Studies 316
12.8 Conclusions 316
References 318
Part Three Codrugs and Soft Drugs 345
13 Improving the Use of Drug Combinations Through the Codrug Approach 347
Peter A. Crooks, Harpreet K. Dhooper, and Ujjwal Chakraborty
13.1 Codrugs and Codrug Strategy 347
13.2 Ideal Codrug Characteristics 348
13.3 Examples of Marketed Codrugs 349
13.4 Topical Codrug Therapy for the Treatment of Ophthalmic Diseases 351
13.4.1 Codrugs for the Treatment of Diabetic Retinopathy 351
13.4.2 Codrugs Containing Corticosteroids for Proliferative Vitreoretinopathy 353
13.4.3 Codrugs Containing Nonsteroidal Anti-Inflammatory Agents for Treatment of Proliferative Vitreoretinopathy 355
13.4.4 Codrugs Containing Ethacrynic Acid for Treatment of Elevated Intraocular Pressure 356
13.5 Codrugs for Transdermal Delivery 357
13.5.1 Codrugs for the Treatment of Alcohol Abuse and Tobacco Dependence 357
13.5.2 Duplex Codrugs of Naltrexone for Transdermal Delivery 362
13.5.3 Codrugs Containing a-Tocopherol for Skin Hydration 362
13.6 Codrugs of L-DOPA for the Treatment of Parkinson's Disease 363
13.6.1 L-DOPA Codrugs that Incorporate Inhibitors of L-DOPA Metabolism 363
13.6.2 L-DOPA-Antioxidant Codrugs 364
13.7 Analgesic Codrugs Containing Nonsteroidal Anti-Inflammatory Agents 367
13.7.1 Flurbiprofen-Histamine H2 Antagonist Codrugs 367
13.7.2 NSAID-Acetaminophen Codrugs 368
13.7.3 Naproxen-Propyphenazone Codrugs 370
13.7.4 Flurbiprofen-Amino Acid Codrugs 371
13.7.5 NSAID-Chlorzoxazone Codrugs 372
13.7.6 Acetaminophen-Chlorzoxazone Codrug 373
13.8 Analgesic Codrugs of Opioids and Cannabinoids 373
13.9 Codrugs Containing Anti-HIV Drugs 375
13.9.1 AZT-Retinoic Acid Codrug 377
References 378
14 Soft Drugs 385
Paul W. Erhardt and Michael D. Reese
14.1 Introduction 385
14.1.1 Definition 385
14.1.2 Prototypical Agent 386
14.1.2.1 Backdrop 386
14.1.2.2 Clinical Challenge 386
14.1.2.3 Pharmacological Target 388
14.1.2.4 Pharmacology, Human Pharmacokinetic Profile, and Clinical Deployment 389
14.2 Indications 390
14.2.1 A Huge Potential 391
14.2.2 ''To Market, To Market'' 392
14.3 Design Considerations 396
14.3.1 General Requirements 396
14.3.2 Enzymatic Aspects 397
14.3.3 Chemical Structural Aspects 397
14.4 Case Study: The Discovery of Esmolol 400
14.4.1 Internal Esters 400
14.4.2 External Esters 402
14.4.3 ''Square Pegs and Round Holes'' 402
14.4.4 Surrogate Scaffolds for Testing Purposes and a ''Glimmer of Hope'' 403
14.4.5 A ''Goldilocks'' Compound Called Esmolol 404
14.4.6 ''Esmolol Stat'' 406
14.4.7 Case Study Summary and Some Take-Home Lessons for Today 407
14.4.7.1 Compound Libraries 407
14.4.7.2 Biological Testing 408
14.4.7.3 SAR 408
14.5 Summary 408
References 409
Part Four Preclinical and Clinical Consideration for Prodrugs 415
15 Pharmacokinetic and Biopharmaceutical Considerations in Prodrug Discovery and Development 417
John P. O'Donnell
15.1 Introduction 417
15.2 Understanding Pharmacokinetic/Pharmacodynamic Relationships 417
15.3 Pharmacokinetics 418
15.4 Tools for the Prodrug Scientist 421
15.4.1 Bioanalytical Assay Development 421
15.4.2 Use of Radiolabel 422
15.5 Enzymes Involved with Prodrug Conversion 423
15.5.1 Carboxylesterases 423
15.5.2 Alkaline Phosphatase 426
15.5.3 Cytochrome P450 428
15.6 Use of the Caco-2 System for Permeability and Active Transport Evaluation 428
15.7 XP13512: Improving PK Performance by Targeting Active Transport 432
15.8 Prodrug Absorption: Transport/Metabolic Conversion Interplay 434
15.8.1 Pivampicillin 434
15.8.2 Valacyclovir 436
15.9 Preabsorptive Degradation 438
15.9.1 Cephalosporin Prodrugs 438
15.9.2 Sulopenem Prodrugs PF-00398899, PF-03709270, and PF-04064900 439
15.10 Biopharmaceutical-Based PK Modeling for Prodrug Design 440
15.11 Conclusions 447
References 447
16 The Impact of Pharmacogenetics on the Clinical Outcomes of Prodrugs 453
Jane P.F. Bai, Mike Pacanowski, Atiqur Rahman, and Lawrence L. Lesko
16.1 Introduction 453
16.2 Clopidogrel and CYP2C19 454
16.2.1 Summary 457
16.3 Codeine and CYP2D6 457
16.3.1 Summary 460
16.4 Tamoxifen and CYP2D6 460
16.4.1 Summary 463
16.5 Fluorouracil Prodrugs and Carboxylesterase 464
16.5.1 Capecitabine and Carboxylesterase 465
16.5.1.1 Summary 467
16.5.2 Tegafur and CYP2A6 467
16.5.2.1 Summary 468
16.6 Irinotecan and Carboxylesterase 2 468
16.6.1 Summary 469
16.7 Others 470
16.7.1 ACE Inhibitors and CES 470
16.7.2 Cyclophosphamide and CYP2B6/CYP2C19 470
16.7.2.1 Summary 471
16.8 Drug Development Implication 471
16.9 Conclusions 473
References 473
Index 483
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