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Prodrugs and Targeted Delivery


Prodrugs and Targeted Delivery

Towards Better ADME Properties
Methods & Principles in Medicinal Chemistry, Band 47 1. Aufl.

von: Jarkko Rautio, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

165,99 €

Verlag: Wiley-VCH
Format: PDF
Veröffentl.: 29.11.2010
ISBN/EAN: 9783527633173
Sprache: englisch
Anzahl Seiten: 520

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Beschreibungen

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

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Kunststoffe
Kunststoffe
von: Wilhelm Keim
PDF ebook
99,99 €