Prodrugs and targeted delivery : towards better ADME properties

Author(s)

    • Rautio, Jarkko

Bibliographic Information

Prodrugs and targeted delivery : towards better ADME properties

edited by Jarkko Rautio

(Methods and principles in medicinal chemistry / edited by R. Mannhold ... [et al.], v. 47)

Wiley-VCH, c2011

Available at  / 5 libraries

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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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