Prodrugs and Targeted Delivery: Towards Better ADME Properties / Edition 1

Prodrugs and Targeted Delivery: Towards Better ADME Properties / Edition 1

ISBN-10:
3527326030
ISBN-13:
9783527326037
Pub. Date:
01/31/2011
Publisher:
Wiley
ISBN-10:
3527326030
ISBN-13:
9783527326037
Pub. Date:
01/31/2011
Publisher:
Wiley
Prodrugs and Targeted Delivery: Towards Better ADME Properties / Edition 1

Prodrugs and Targeted Delivery: Towards Better ADME Properties / Edition 1

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Overview

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.

Product Details

ISBN-13: 9783527326037
Publisher: Wiley
Publication date: 01/31/2011
Series: Methods & Principles in Medicinal Chemistry , #47
Pages: 520
Product dimensions: 6.90(w) x 9.60(h) x 1.20(d)

About the Author

Jarkko Rautio is professor of pharmaceutical chemistry and head of the multidisciplinary Pharmaceutical and Medicinal Chemistry (PMC) research group at the School of Pharmacy, University of Eastern Finland (formerly University of Kuopio), where he received his PhD in pharmaceutical chemistry in 2000. He subsequently carried out his postdoctoral studies at the University of Maryland, Baltimore, USA, and was a visiting scientist at GlaxoSmithKline, North Carolina, while also co-founding the American Association of Pharmaceutical Scientists (AAPS) Prodrug Focus Group in 2005. Professor Rautio's research focuses on chemistry-based methods, especially prodrugs, to overcome the liabilities of drugs.

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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