Del 47 - Methods & Principles in Medicinal Chemistry
Prodrugs and Targeted Delivery
Towards Better ADME Properties
Inbunden, Engelska, 2010
Av Jarkko Rautio, Finland) Rautio, Jarkko (University of Eastern Finland, Kuopio
2 449 kr
Produktinformation
- Utgivningsdatum2010-12-15
- Mått173 x 244 x 41 mm
- Vikt1 429 g
- FormatInbunden
- SpråkEngelska
- SerieMethods & Principles in Medicinal Chemistry
- Antal sidor520
- FörlagWiley-VCH Verlag GmbH
- ISBN9783527326037
Tillhör följande kategorier
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.
- List of Contributors XVIIPreface XXIA Personal Foreword XXIIIPart One Prodrug Design and Intellectual Property 11 Prodrug Strategies in Drug Design 3Jarkko Rautio1.1 Prodrug Concept 31.2 Basics of Prodrug Design 41.3 Rationale for Prodrug Design 51.3.1 Overcoming Formulation and Administration Problems 61.3.2 Overcoming Absorption Barriers 81.3.3 Overcoming Distribution Problems 91.3.4 Overcoming Metabolism and Excretion Problems 101.3.5 Overcoming Toxicity Problems 101.3.6 Life Cycle Management 131.4 History of Prodrug Design 141.5 Recently Marketed Prodrugs 171.5.1 Prodrug Prevalence 171.5.2 Recent Prodrug Approvals 171.6 Concluding Remarks 25References 262 The Molecular Design of Prodrugs by Functional Group 31Victor R. Guarino2.1 Introduction 312.2 The Prodrug Concept and Basics of Design 322.3 Common Functional Group Approaches in Prodrug Design 342.3.1 Aliphatic and Aromatic Alcohols 342.3.1.1 Phosphate Monoesters 352.3.1.2 Simple Acyl Esters 372.3.1.3 Amino Acid Esters 382.3.1.4 Other Ester-Based Approaches 392.3.2 Carboxylic Acids 402.3.2.1 Alkyl Esters 412.3.2.2 Aminoalkyl Esters 422.3.2.3 Spacer Groups to Alleviate Steric Hindrance 422.3.3 Imides, Amides, and Other NH Acids 432.3.3.1 Imide-Type NH Acids 442.3.3.2 Amide-Type NH Acids 442.3.3.3 Sulfonamide NH Acids 482.3.4 Phosphates, Phosphonates, and Phosphinates 492.3.4.1 Simple Alkyl and Aryl Esters 492.3.4.2 Acyloxyalkyl and Alkoxycarbonyloxyalkyl Esters 502.3.4.3 Aryl Phospho(n/r)amidates and Phospho(n/r)diamides 512.3.4.4 HepDirect Technology 532.3.5 Amines and Benzamidines 532.3.5.1 N-Acyloxyalkoxycarbonyl Prodrugs 542.3.5.2 N-Mannich Bases 552.3.5.3 N-Acyloxyalkyl and N-Phosphoryloxyalkyl Prodrugs of Tertiary Amines 552.3.5.4 N-Hydroxy and Other Modifications for Benzamidines 562.4 Conclusions 56References 573 Intellectual Property Primer on Pharmaceutical Patents with a Special Emphasis on Prodrugs and Metabolites 61Eyal H. Barash3.1 Introduction 613.2 Patents and FDA Approval Process 613.3 Obtaining a Patent 653.3.1 Utility 663.3.2 Novelty 673.3.3 Nonobviousness 713.4 Conclusion 78Part Two Prodrugs Addressing ADMET Issues 794 Increasing Lipophilicity for Oral Drug Delivery 81Majid Y. Moridani4.1 Introduction 814.2 pKa, Degree of Ionization, Partition Coefficient, and Distribution Coefficient 814.3 Prodrug Strategies to Enhance Lipid Solubility 854.4 Prodrug Examples for Antibiotics 874.4.1 Bacampicillin 874.4.2 Carindacillin 884.4.3 Cefditoren Pivoxil 894.4.4 Cefuroxime Axetil 904.4.5 Cefpodoxime Proxetil 914.5 Antiviral Related Prodrugs 924.5.1 Oseltamivir 924.5.2 Famciclovir 924.5.3 Adefovir Dipivoxil 934.5.4 Tenofovir Disoproxil 944.6 Cardiovascular Related Prodrugs 954.6.1 Enalapril 954.6.2 Fosinopril 964.6.3 Olmesartan Medoxomil 974.7 Lipophilic Prodrugs of Benzamidine Drugs 984.7.1 Ximelagatran 984.7.2 Dabigatran Etexilate 994.8 Miscellaneous Examples 1004.8.1 Capecitabine 1004.8.2 Mycophenolate Mofetil 1014.8.3 Misoprostol 1024.8.4 Additional Examples 1024.9 Summary and Conclusion 104References 1065 Modulating Solubility Through Prodrugs for Oral and IV Drug Delivery 111Victor R. Guarino5.1 Introduction 1115.2 Basics of Solubility and Oral/IV Drug Delivery 1125.2.1 Some Basic Fundamentals of Solubility 1125.2.2 Some General Comments on IV Drug Delivery 1145.2.3 Some General Comments on Oral Drug Delivery 1165.3 Prodrug Applications for Enhanced Aqueous Solubility 1175.3.1 Prodrug Concept 1175.3.2 Examples of Prodrugs to Enhance Aqueous Solubility for IV Administration 1185.3.2.1 Fosphenytoin 1185.3.2.2 Fospropofol 1195.3.2.3 Parecoxib 1205.3.2.4 Irinotecan 1205.3.3 Prodrugs to Enhance Aqueous Solubility for Oral Administration 1215.3.3.1 Fosamprenavir 1215.3.3.2 Valganciclovir 1225.4 Challenges with Solubilizing Prodrugs of Insoluble Drugs 1235.4.1 Challenges with Solubilizing Prodrug Strategies for IV Administration 1235.4.2 Challenges with Solubilizing Prodrug Strategies for Oral Administration 1245.5 Additional Applications of Prodrugs for Modulating Solubility 1255.5.1 Alleviating pH-Dependent Oral Bioavailability of Weakly Basic Drugs 1265.5.2 Aligning pH-Solubility and pH-Stability Relationships for IV Products 1265.5.3 Modulating Solubility in Negative Direction 1275.6 Parallel Exploration of Analogues and Prodrugs in Drug Discovery (Commentary) 1285.7 Conclusions 129References 1296 Prodrugs Designed to Target Transporters for Oral Drug Delivery 133Mark S. Warren and Jarkko Rautio6.1 Introduction 1336.2 Serendipity: An Actively Transported Prodrug 1336.3 Requirements for Actively Transported Prodrugs 1356.4 Peptide Transporters: PEPT1 and PEPT2 1356.5 Monocarboxylate Transporters 1406.6 Bile Acid Transporters 1436.7 Conclusions 147References 1477 Topical and Transdermal Delivery Using Prodrugs: Mechanism of Enhancement 153Kenneth Sloan, Scott C. Wasdo, and Susruta Majumdar7.1 Introduction 1537.2 Arrangement of Water in the Stratum Corneum 1557.3 A New Model for Diffusion Through the Stratum Corneum: The Biphasic Solubility Model 1567.4 Equations for Quantifying Effects of Solubility on Diffusion Through the Stratum Corneum 1587.4.1 The Roberts–Sloan Equation When the Vehicle is Water 1597.4.2 The Roberts–Sloan Equation When the Vehicle is a Lipid 1607.4.3 The Series/Parallel Equation When the Vehicle is a Lipid 1617.5 Design of Prodrugs for Topical and Transdermal Delivery Based on the Biphasic Solubility Model 1627.5.1 5-Fluorouracil Prodrugs 1647.5.1.1 N-Acyl 5-FU Prodrugs 1657.5.1.2 N-Soft Alkyl 5-FU Prodrugs 1667.5.2 Acetaminophen (APAP) Prodrugs 1677.5.2.1 O-Acyl APAP Prodrugs 1687.5.2.2 O-Soft Alkyl APAP Prodrugs 1707.5.3 S-Soft Alkyl Prodrugs of 6-Mercaptopurine 1707.5.3.1 Effect of Vehicles on Topical and Transdermal Delivery 1717.6 Comparison of Human and Mouse Skin Experiments 1727.7 Summary 174References 1758 Ocular Delivery Using Prodrugs 181Deep Kwatra, Ravi Vaishya, Ripal Gaudana, Jwala Jwala, and Ashim K. Mitra8.1 Introduction 1818.2 Criteria for an Ideal Ophthalmic Prodrug 1818.3 Anatomy and Physiology of the Eye 1828.3.1 Anterior Chamber 1838.3.2 Posterior Chamber 1838.4 Barriers to Ocular Drug Delivery 1848.4.1 Tear Film 1848.4.2 Corneal Epithelium 1848.4.3 Aqueous Humor and BAB 1848.4.4 Conjunctiva 1848.4.5 Blood–Retinal Barrier 1858.5 Influx and Efflux Transporters on the Eye 1858.6 Transporter-Targeted Prodrug Approach 1868.6.1 Acyclovir 1868.6.2 Ganciclovir 1888.6.3 Quinidine 1888.7 Drug Disposition in Ocular Delivery 1898.8 Effect of Physiochemical Factors on Drug Disposition in Eye 1908.9 Prodrug Strategy to Improve Ocular Bioavailability (Nontransporter-Targeted Approach) 1928.9.1 Epinephrine 1928.9.2 Phenylephrine 1928.9.3 Pilocarpine 1938.9.4 Timolol 1958.9.5 Prostaglandin F2a 1978.10 Recent Patents and Marketed Ocular Prodrugs 1988.11 Novel Formulation Approaches for Sustained Delivery of Prodrugs 2018.12 Conclusion 201References 2029 Reducing Presystemic Drug Metabolism 207Majid Y. Moridani9.1 Introduction 2079.2 Presystemic Metabolic Barriers 2099.2.1 Esterases 2099.2.2 Cytochrome P450 Enzymes 2129.2.3 Phase II Drug Metabolizing Enzymes 2149.2.4 Peptidases 2159.2.5 Other Oxidative Metabolizing Enzymes 2169.3 Prodrug Approaches to Reduce Presystemic Drug Metabolism 2179.4 Targeting Colon 2209.5 Targeting Lymphatic Route 2219.6 Conclusion 225References 22610 Enzyme-Activated Prodrug Strategies for Site-Selective Drug Delivery 231Krista Laine and Kristiina Huttunen10.1 Introduction 23110.2 General Requirements for Enzyme-Activated Targeted Prodrug Strategy 23210.3 Examples of Targeted Prodrug Strategies 23210.3.1 Tumor-Selective Prodrugs 23210.3.1.1 Prodrugs Activated by Hypoxia-Associated Reductive Enzymes 23310.3.1.2 Prodrugs Activated by Glutathione S-Transferase 23610.3.1.3 Prodrugs Activated by Thymidine Phosphorylase 23710.3.2 Organ-Selective Prodrugs 23910.3.2.1 Liver-Targeted Prodrugs 23910.3.2.2 Kidney-Targeted Prodrugs 24210.3.2.3 Colon-Targeted Prodrugs 24310.3.3 Virus-Selective Prodrugs 24410.4 Summary 245References 24611 Prodrug Approaches for Central Nervous System Delivery 253Quentin R. Smith and Paul R. Lockman11.1 Blood–Brain Barrier in CNS Drug Development 25311.2 Prodrug Strategies 25511.3 Prodrug Strategies Based Upon BBB Nutrient Transporters 25711.4 Prodrug Strategies Based Upon BBB Receptors 26311.5 CNS Prodrug Summary 264References 26612 Directed Enzyme Prodrug Therapies 271Dan Niculescu-Duvaz, Gabriel Negoita-Giras, Ion Niculescu-Duvaz, Douglas Hedley, and Caroline J. Springer12.1 Introduction 27112.2 Theoretical Background of DEPT 27112.2.1 ADEPT and Other Enzyme–Conjugates Approaches 27212.2.2 LIDEPT 27312.2.3 GDEPT and Other Gene Delivery Approaches 27312.2.4 BDEPT 27512.3 Comparison of ADEPT and GDEPT 27512.4 Enzymes in ADEPT and GDEPT 27812.5 Design of Prodrugs 28212.5.1 Mechanisms of Prodrug Activation 28212.5.1.1 Electronic Switch 28212.5.1.2 Cell Exclusion 28512.5.1.3 Blockage of the Pharmacophore 28512.5.1.4 Conversion to Substrate for Endogenous Enzymes 28712.5.1.5 Formation of a Reactive Moiety 28712.5.1.6 Formation of a Second Interactive Group 28812.5.2 Enzymatic Reactions Activating the Prodrug. The Trigger 28812.5.2.1 Reactions Catalyzed by Hydrolases: Hydrolytic Cleavage 28912.5.2.2 Activation by Nucleotide Phosphorylation 29012.5.2.3 Activation by Reductases 29012.5.2.4 Activation by Oxidases 29112.5.2.5 (Deoxy)Ribosyl Transfer 29112.5.3 The Linker. Self-Immolative Prodrugs 29212.5.3.1 Self-Immolative Prodrugs Fragmenting by Elimination 29312.5.3.2 Linker–Drug Connection 29312.5.3.3 Self-Immolative Prodrugs Fragmenting Following Cyclization 29612.6 Strategies Used for the Improvement of DEPT Systems 29612.6.1 Improvement of the Prodrug 29612.6.1.1 Cytotoxicity Differential 29712.6.1.2 Stability of Prodrugs 29812.6.1.3 Cytotoxicity and Mechanism of Action of the Released Drug 29912.6.1.4 Stability of the Released Drug 29912.6.1.5 Resistance (Prodrug Related) 30012.6.1.6 Kinetics of Activation 30012.6.1.7 Physicochemical Properties 30212.6.1.8 Pharmacokinetics 30312.6.1.9 Specificity of Enzyme Activation 30412.6.2 Improving the Enzymes 30412.6.3 The Multigene Approach 30512.6.4 Enhancing the Immune Response 30712.7 Biological Data for ADEPT and GDEPT 30712.7.1 Bacteria 30812.7.2 Viruses 30812.7.3 Adenoviral Vectors 30812.7.4 Pox Viral Vectors 30912.7.5 Adeno-Associated Viral Vectors 30912.7.6 Retroviral Vectors 30912.7.7 Lentiviral Vectors 31012.7.8 Measles Viral Vectors 31012.7.9 Herpes Simplex Viral Vectors 31112.7.10 Neural Stem Cells/Progenitor Cells 31112.7.11 Liposomes 31112.7.12 ADEPT Vectors 31212.7.13 Vectors for Prodrugs 31212.7.14 Clinical Studies 31612.8 Conclusions 316References 318Part Three Codrugs and Soft Drugs 34513 Improving the Use of Drug Combinations Through the Codrug Approach 347Peter A. Crooks, Harpreet K. Dhooper, and Ujjwal Chakraborty13.1 Codrugs and Codrug Strategy 34713.2 Ideal Codrug Characteristics 34813.3 Examples of Marketed Codrugs 34913.4 Topical Codrug Therapy for the Treatment of Ophthalmic Diseases 35113.4.1 Codrugs for the Treatment of Diabetic Retinopathy 35113.4.2 Codrugs Containing Corticosteroids for Proliferative Vitreoretinopathy 35313.4.3 Codrugs Containing Nonsteroidal Anti-Inflammatory Agents for Treatment of Proliferative Vitreoretinopathy 35513.4.4 Codrugs Containing Ethacrynic Acid for Treatment of Elevated Intraocular Pressure 35613.5 Codrugs for Transdermal Delivery 35713.5.1 Codrugs for the Treatment of Alcohol Abuse and Tobacco Dependence 35713.5.2 Duplex Codrugs of Naltrexone for Transdermal Delivery 36213.5.3 Codrugs Containing a-Tocopherol for Skin Hydration 36213.6 Codrugs of L-DOPA for the Treatment of Parkinsons Disease 36313.6.1 L-DOPA Codrugs that Incorporate Inhibitors of L-DOPA Metabolism 36313.6.2 L-DOPA–Antioxidant Codrugs 36413.7 Analgesic Codrugs Containing Nonsteroidal Anti-Inflammatory Agents 36713.7.1 Flurbiprofen–Histamine H2 Antagonist Codrugs 36713.7.2 NSAID–Acetaminophen Codrugs 36813.7.3 Naproxen–Propyphenazone Codrugs 37013.7.4 Flurbiprofen–Amino Acid Codrugs 37113.7.5 NSAID–Chlorzoxazone Codrugs 37213.7.6 Acetaminophen–Chlorzoxazone Codrug 37313.8 Analgesic Codrugs of Opioids and Cannabinoids 37313.9 Codrugs Containing Anti-HIV Drugs 37513.9.1 AZT–Retinoic Acid Codrug 377References 37814 Soft Drugs 385Paul W. Erhardt and Michael D. Reese14.1 Introduction 38514.1.1 Definition 38514.1.2 Prototypical Agent 38614.1.2.1 Backdrop 38614.1.2.2 Clinical Challenge 38614.1.2.3 Pharmacological Target 38814.1.2.4 Pharmacology, Human Pharmacokinetic Profile, and Clinical Deployment 38914.2 Indications 39014.2.1 A Huge Potential 39114.2.2 ‘‘To Market, To Market’’ 39214.3 Design Considerations 39614.3.1 General Requirements 39614.3.2 Enzymatic Aspects 39714.3.3 Chemical Structural Aspects 39714.4 Case Study: The Discovery of Esmolol 40014.4.1 Internal Esters 40014.4.2 External Esters 40214.4.3 ‘‘Square Pegs and Round Holes’’ 40214.4.4 Surrogate Scaffolds for Testing Purposes and a ‘‘Glimmer of Hope’’ 40314.4.5 A ‘‘Goldilocks’’ Compound Called Esmolol 40414.4.6 ‘‘Esmolol Stat’’ 40614.4.7 Case Study Summary and Some Take-Home Lessons for Today 40714.4.7.1 Compound Libraries 40714.4.7.2 Biological Testing 40814.4.7.3 SAR 40814.5 Summary 408References 409Part Four Preclinical and Clinical Consideration for Prodrugs 41515 Pharmacokinetic and Biopharmaceutical Considerations in Prodrug Discovery and Development 417John P. O’Donnell15.1 Introduction 41715.2 Understanding Pharmacokinetic/Pharmacodynamic Relationships 41715.3 Pharmacokinetics 41815.4 Tools for the Prodrug Scientist 42115.4.1 Bioanalytical Assay Development 42115.4.2 Use of Radiolabel 42215.5 Enzymes Involved with Prodrug Conversion 42315.5.1 Carboxylesterases 42315.5.2 Alkaline Phosphatase 42615.5.3 Cytochrome P450 42815.6 Use of the Caco-2 System for Permeability and Active Transport Evaluation 42815.7 XP13512: Improving PK Performance by Targeting Active Transport 43215.8 Prodrug Absorption: Transport/Metabolic Conversion Interplay 43415.8.1 Pivampicillin 43415.8.2 Valacyclovir 43615.9 Preabsorptive Degradation 43815.9.1 Cephalosporin Prodrugs 43815.9.2 Sulopenem Prodrugs PF-00398899, PF-03709270, and PF-04064900 43915.10 Biopharmaceutical-Based PK Modeling for Prodrug Design 44015.11 Conclusions 447References 44716 The Impact of Pharmacogenetics on the Clinical Outcomes of Prodrugs 453Jane P.F. Bai, Mike Pacanowski, Atiqur Rahman, and Lawrence L. Lesko16.1 Introduction 45316.2 Clopidogrel and CYP2C19 45416.2.1 Summary 45716.3 Codeine and CYP2D6 45716.3.1 Summary 46016.4 Tamoxifen and CYP2D6 46016.4.1 Summary 46316.5 Fluorouracil Prodrugs and Carboxylesterase 46416.5.1 Capecitabine and Carboxylesterase 46516.5.1.1 Summary 46716.5.2 Tegafur and CYP2A6 46716.5.2.1 Summary 46816.6 Irinotecan and Carboxylesterase 2 46816.6.1 Summary 46916.7 Others 47016.7.1 ACE Inhibitors and CES 47016.7.2 Cyclophosphamide and CYP2B6/CYP2C19 47016.7.2.1 Summary 47116.8 Drug Development Implication 47116.9 Conclusions 473References 473Index 483
"The book captures all the important aspects of prodrugs. It is well organized in that each chapter presents a specific topic with very little duplication of contents between chapters . . . Given the fact that prodrugs are now increasingly integrated into early drug discovery, this type of book would be a valuable addition to the library of any drug discovery institution." (Journal of Medicinal Chemistry, 8 August 2011) "Every company employing medicinal chemists will be interested in this practice-oriented overview of a key strategy in modern drug discovery and development." (Pharmiweb, 16 February 2011)
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