NICHOLAS BODOR is Graduate Research Professor Emeritus (active) at the University of Florida. He has over 500 publications and 220 patents to his credit. His many awards include the Florida Scientist of the Year, the Volweiler Award, the Distinguished Pharmaceutical Scientist Award, the Fabinyi Prize, and the Commander's Cross of the Order of Merit of Hungary. He holds numerous honorary doctor degrees. He was elected to the Hungarian Academy of Sciences and inducted to the ACS Medicinal Chemistry Hall of Fame.

PETER BUCHWALD is Assistant Professor in the Department of Molecular and Cellular Pharmacology and Director of Drug Discovery for the Diabetes Research Institute at the University of Miami. He is the author of nine book chapters and eighty-six peer-reviewed publications.

Innovative approach to drug design that's more likely to result in an approvable drug product
Retrometabolic drug design incorporates two distinct drug design approaches to obtain soft drugs and chemical delivery systems, respectively. Combining fundamentals with practical step-by-step examples, Retrometabolic Drug Design and Targeting gives readers the tools they need to take full advantage of retrometabolic approaches in order to develop safe and effective targeted drug therapies. The authors, both pioneers in the fields of soft drugs and retrometabolic drug design, offer valuable ideas, approaches, and solutions to a broad range of challenges in drug design, optimization, stability, side effects, and toxicity.
Retrometabolic Drug Design and Targeting begins with an introductory chapter that explores new drugs and medical progress as well as the challenges of today's drug discovery. Next, it discusses:
* Basic concepts of the mechanisms of drug action
* Drug discovery and development processes
* Retrometabolic drug design
* Soft drugs
* Chemical delivery systems
Inside the book, readers will find examples from different pharmacological areas detailing the rationale for each drug design. These examples set forth the relevant pharmacokinetic and pharmacodynamic properties of the new therapeutic agents, comparing these properties to those of other compounds used for the same therapeutic purpose. In addition, the authors review dedicated computer programs that are available to support and streamline retrometabolic drug design efforts.
Retrometabolic Drug Design and Targeting is recommended for all drug researchers interested in employing this newly tested and proven approach to developing safe and effective drugs.

Preface ix

1 Introduction 1

1.1 New Drugs and Medical Progress 1

1.2 The Challenge of New Drug Discovery 5

References 7

2 Mechanism of Drug Action: Basic Concepts 9

2.1 Pharmacodynamic Phase: Drug-Receptor Interactions 10

2.1.1 The Receptor Concept and Receptor Types 10

2.1.2 Ligand-Receptor Binding 12

2.1.3 Receptor Occupancy and Activation 16

2.2 Pharmacokinetic Phase: ADME 20

2.2.1 Drug Absorption and Distribution 20

2.2.2 Drug Metabolism and Excretion 22

2.2.3 Basic Pharmacokinetic Concepts 26

2.3 Structural Requirements: Keeping It "Drug-Like" 29

2.3.1 The Drug-Like Chemical Space 29

2.3.2 Oral Drugs: The Challenge of Bioavailability 31

References 33

3 The Drug Discovery and Development Process 39

3.1 Discovery Research 39

3.1.1 Prediscovery 39

3.1.2 Target Identification 41

3.1.3 Target Validation 42

3.1.4 Target-to-Hit and Hit-to-Lead Development 42

3.1.5 Early Distribution and Safety Tests 46

3.1.6 Lead Optimization 48

3.2 Preclinical Development 49

3.2.1 Preclinical Testing 49

3.2.2 Investigational New Drug Application and Safety 50

3.3 Clinical Development 51

3.3.1 Phase I Clinical Trials 51

3.3.2 Phase II Clinical Trials 51

3.3.3 Phase III Clinical Trials 52

3.4 Regulatory Approval and PostMarketing Development 53

3.4.1 New Drug Application and Regulatory Approval 53

3.4.2 Manufacturing 54

3.4.3 Postapproval Studies and Phase IV Trials 54

3.4.4 Patent Expiration and Generic Approval 54

3.5 Problems with the Current Paradigm 56

3.5.1 Decreasing R&D Efficiency 56

3.5.2 The Drug Discovery Process: Improvements Needed 62

References 64

4 Retrometabolic Drug Design 71

4.1 Design Principles 71

4.2 Terminology 72

4.2.1 Soft Drug vs. Hard Drug 72

4.2.2 Soft Drug vs. Prodrug 73

4.2.3 Chemical Delivery System vs. Prodrug 73

References 74

5 Soft Drugs 77

5.1 Enzymatic Hydrolysis 78

5.1.1 Esterases 79

5.1.2 Interspecies Variability 81

5.1.3 Interorgan and Interindividual Variability 82

5.1.4 Mechanism: Catalytic Triad and Oxyanion Hole 83

5.1.5 Kinetics 84

5.1.6 Stereoselectivity 85

5.1.7 Activation Energy and Temperature Dependence 85

5.1.8 Structure-Metabolism Relationships 86

5.1.9 Rate-Influencing Role of the Alcohol or Acyl Side Chain 92

5.2 Soft Drug Approaches 93

5.3 Inactive Metabolite-Based Soft Drugs 96

5.3.1 Soft Beta-Blockers 97

5.3.2 Soft Opioid Analgetics: Remifentanil 106

5.3.3 Soft Corticosteroids 109

5.3.4 Soft Calcitriol (1,25-Dihydroxyvitamin D3) Analogs 137

5.3.5 Soft Estrogens 138

5.3.6 Soft 2-Agonists 140

5.3.7 Soft Psychostimulants 142

5.3.8 Soft Insecticides and Pesticides 144

5.3.9 Soft Anticholinergics: Inactive Metabolite-Based Approach 147

5.4 Soft Analogs 151

5.4.1 Soft Anticholinergics: Soft Quaternary Analogs 152

5.4.2 Soft Antimicrobials 154

5.4.3 Soft Antiarrhythmic Agents 156

5.4.4 Soft Serotonin Receptor Agonists: Naronapride 160

5.4.5 Soft Anticoagulants (Vitamin K Antagonists): Tecarfarin 162

5.4.6 Soft Angiotensin Converting Enzyme Inhibitors 164

5.4.7 Soft Dihydrofolate Reductase Inhibitors 165

5.4.8 Soft Calcineurin Inhibitors (Soft Immunosuppressants) 166

5.4.9 Soft Cytokine Modulators 169

5.4.10 Soft Phosphodiesterase 4 Inhibitors 171

5.4.11 Soft Matrix Metalloproteinase Inhibitors 173

5.4.12 Soft Cannabinoids 173

5.4.13 Soft Benzodiazepine Analogs: Remimazolam and Analogs 175

5.4.14 Soft Anesthetics 178

5.4.15 Soft Ca2+ Channel Blockers 182

5.5 Active Metabolite-Based Soft Drugs 184

5.6 Activated Soft Drugs 186

5.7 Pro-Soft Drugs 188

5.7.1 Pro-Soft Drugs of Natural Soft Drugs: Hormone Prodrugs 188

5.7.2 Pro-Soft Drugs of Peptidyl Boronic Acid Derivatives 188

5.8 Computer-Aided Design 191

5.8.1 Computer-Aided Soft Drug Design 192

5.8.2 Predicting Molecular Properties 194

5.8.3 Molecular Size 194

5.8.4 Lipophilicity: Octanol/Water Partition Coefficient 196

5.8.5 Water Solubility 205

5.8.6 Structure Generation 206

5.8.7 Candidate Ranking 206

5.8.8 Hydrolytic Lability 208

5.8.9 Illustrations 209

5.9 Soft Drugs: Summary 215

References 215

6 Chemical Delivery Systems 259

6.1 Enzymatic Physicochemical-Based (Brain-Targeting) CDSs 260

6.1.1 The Challenge of Brain Targeting 260

6.1.2 The Blood-Brain Barrier 260

6.1.3 Brain-Targeting Drug Delivery Approaches 263

6.1.4 Brain-Targeting CDSs: Details 274

6.1.5 Quantifying Delivery 282

6.1.6 Genesis of the CDS Concept: Pro-2-PAM 284

6.1.7 Berberine 288

6.1.8 Dopamine CDS 290

6.1.9 Zidovudine (AZT) CDS 292

6.1.10 Other Antiviral and Antiretroviral CDSs 294

6.1.11 Anticancer CDSs 299

6.1.12 Other Brain-Targeting CDSs 302

6.1.13 Estradiol CDS 307

6.1.14 Cyclodextrin Complexes 328

6.1.15 Molecular Packaging 331

6.2 Site-Specific Enzyme-Activated (Eye-Targeting) CDSs 346

6.2.1 The Challenge of Ocular Targeting 346

6.2.2 Potential Therapeutic Applications: Glaucoma 347

6.2.3 Eye-Targeting CDSs: Design Principles 348

6.2.4 Oxime and Methoxime Analogs of Beta-Blockers 350

6.3 Receptor-Based Transient Anchor-Type CDSs 357

References 358

Conclusions 395

Index 397