药物化学 英中双语注解版PDF电子书下载

1 Drug Discovery,Design and Development 1

1.1 Drug Discovery 1

1.1.1 A Drug Discovery without a Lead 2

1.1.2 Lead Discovery 4

1.2 Lead Modification 8

1.2.1 Identification of the Active Part:The Pharmacophore 8

1.2.2 Structure Modifications to Increase Potency and the Therapeutic Index 11

1.3 New Drug Development 19

1.3.1 General Process of New Drug Development 19

1.3.2 Preclinical Development and Investigational New Drug Application 21

1.4 Problems 22

本章重点内容 23

2 Receptors 24

2.1 Drug-Receptor Interactions 24

2.1.1 Interactions(Forces)Involved in the Drug-Receptor Complex 24

2.2 Theories for Drug-Receptor Interactions 32

2.2.1 Induced-Fit Theory 32

2.2.2 The Two-State(Multistate)Model of Receptor Activation 33

2.3 Topographical and Stereochemical Considerations 35

2.3.1 Spatial Arrangement of Atoms 35

2.3.2 Drug and Receptor Chirality 36

2.3.3 Geometric Isomers(Diastereomers) 41

2.3.4 Conformational Isomers 41

2.3.5 Ring Topology 45

2.4 Problems 46

本章重点内容 48

3 Enzymes and Enzyme Inhibition 51

3.1 Enzymes 51

3.1.1 Enzymes as Catalysts 51

3.1.2 Mechanism of Enzyme Catalysis 55

3.1.3 Coenzyme Catalysis 58

3.2 Enzyme Inhibition 61

3.2.1 Enzyme Inhibitors in Medicine 61

3.2.2 Design of Enzyme Inhibitors 62

3.3 Reversible Enzyme Inhibitors 64

3.3.1 Mechanism of Reversible Inhibition 64

3.3.2 Selected Examples of Competitive Reversible Inhibitor Drugs 66

3.3.3 Transition State Analogs 67

3.3.4 Slow,Tight-Binding Inhibitors 68

3.4 Irreversible Enzyme Inhibitors 70

3.4.1 Affinity Labeling Agents 71

3.4.2 Mechanism-Based Enzyme Inactivators 73

3.5 Problems 76

References 77

本章重点内容 78

4 Drug Metabolism 80

4.1 Introduction 80

4.2 Phase Ⅰ Transformations 81

4.2.1 Oxidative Reactions 81

4.2.2 Reductive Reactions 93

4.2.3 Carboxylation Reaction 97

4.2.4 Hydrolytic Reactions 98

4.3 Phase Ⅱ Transformations:Conjugation Reactions 99

4.3.1 Introduction 99

4.3.2 Glucuronic Acid Conjugation 100

4.3.3 Sulfate Conjugation 103

4.3.4 Amino Acid Conjugation 104

4.3.5 Glutathione Conjugation 105

4.3.6 Acetyl Conjugation 107

4.4 Problems 109

本章重点内容 111

5 Prodrugs and Drug Delivery System 113

5.1 Introduction 113

5.1.1 Utility of Prodrugs 113

5.1.2 Types of Prodrugs 115

5.2 Mechanism of Drug Activation 116

5.2.1 Carrier-Linked Prodrugs 116

5.2.2 Bioprecursor Prodrugs 129

5.3 Problems 137

本章重点内容 138

6 Computer Aided Drug Design 139

6.1 Introduction 139

6.1.1 Molecular Mechanics and Empirical Force Field Methods 140

6.1.2 Energy Minimization 142

6.1.3 Conformational Analysis and Search 142

6.2 Structure-Based Drug Design 142

6.2.1 Molecular Graphics-Based Drug Design 143

6.2.2 Molecular Docking 145

6.2.3 De Novo Drugs Design 146

6.3 Ligand Based Drug Design 149

6.3.1 Quantitative Structure-Activity Relationships 149

6.3.2 Pharmacophore Modeling 154

6.4 Problems 159

本章重点内容 160

7 Central Nervous System Drugs 161

7.1 Schizophrenia 161

7.1.1 Introduction 161

7.1.2 Stucture-activity Relationship of Tricyclic Anti-psychotics 165

7.1.3 Typical Drugs 166

7.1.4 Discovery and Development of New Antipsychotic Drugs 168

7.2 Sedative-hypnotics 171

7.2.1 Introduction 171

7.2.2 Stucture-activity Relationship of Benzodiazepines 175

7.2.3 Typical Drugs 177

7.2.4 New Research Areas 181

7.3 Alzheimer's Disease 183

7.3.1 Introduction 183

7.3.2 Typical Drugs 186

7.3.3 New Research Areas 191

7.4 Problems 195

References 195

本章重点内容 197

8 Analgesics and Anesthetics 199

8.1 Analgesics 199

8.1.1 Introduction 199

8.1.2 Opioid Receptor 200

8.1.3 Endogenous Opioid Peptides 200

8.1.4 Morphine and Related Opioids 201

8.1.5 Synthetic Analgesics 204

8.1.6 Unmet Medical Needs 211

8.1.7 New Research Areas 212

8.2 Anesthetics 213

8.2.1 General Anesthetics 213

8.2.2 Local Anesthetics 217

8.2.3 Unmet Medical Needs 222

8.3 Problems 224

本章重点内容 225

9 Drugs for Metabolic Syndrome Treatment 227

9.1 Obesity 227

9.1.1 Current Treatment 227

9.1.2 New Research Areas 228

9.2 Diabetes 228

9.2.1 Current Treatment 230

9.2.2 New Research Areas 242

9.3 Problems 246

References 247

本章重点内容 248

10 Agents for Gastrointestinal Diseases 250

10.1 Introduction 250

10.1.1 The Function of Gastrointestinal Tract 250

10.1.2 Historical Overview 250

10.2 Gastric and Mucosal Ulceration 252

10.2.1 Overview 252

10.2.2 H2 Receptor Antagonists 254

10.2.3 Proton Pump Inhibitors(PPIs) 257

10.2.4 New Research Areas 260

10.3 Inflammatory Bowel Disease 260

10.3.1 Overview 260

10.3.2 New Research Areas 262

10.4 Emesis/Prokinetic Agents 264

10.4.1 Overview 264

10.4.2 New Research Areas 270

10.5 Problems 271

References 271

本章重点内容 272

11 Cardiovascular Agents 274

11.1 Introduction 274

11.2 Hypertension 274

11.2.1 Introduction 274

11.2.2 Antihypertensive Agents 275

11.2.3 New Research Areas 296

11.3 Cardiac Arrhythmias 297

11.3.1 Introduction 297

11.3.2 Antiarrhythmic Agents 298

11.3.3 New Research Areas 303

11.4 Congestive Heart Failure 303

11.4.1 Introduction 303

11.4.2 Cardiac Agents 304

11.5 Angina 306

11.5.1 Introduction 306

11.5.2 Antianginal Agents 306

11.6 Hyperlipidemias 307

11.6.1 Introduction 307

11.6.2 Antihyperlipidemic Agents 308

References 314

选读资料 315

本章重点内容 316

12 Anticancer Agents 318

12.1 Introduction 318

12.2 Current Anticancer Agents 318

12.2.1 Alkylating and Platinum Anticancer Agents 318

12.2.2 Deoxyribonucleic Acid Topoisomerase Inhibitors 329

12.2.3 Antimetabolic Agents 333

12.2.4 Microtubule Targeting Agents 341

12.3 New Research Areas 345

12.3.1 Tyrosine Kinase and Inhibitors 346

12.3.2 Histone Deacetylase Inhibitors 349

12.3.3 Proteasome Inhibitors 351

12.3.4 Other New Research Areas of Anticancer Drugs 351

12.4 Problems 352

References 352

本章重点内容 353

13 Antiviral Agents 356

13.1 Overview of Virus Infections and Antiviral Agents 356

13.2 Antivirals for Herpesviruses 357

13.2.1 Introduction 357

13.2.2 Current Antiherpes Drugs 357

13.2.3 Structure-activity Relationship 359

13.2.4 New Research Areas 362

13.3 Antivirals for Human Immunodeficiency Virus 362

13.3.1 Introduction 362

13.3.2 HIV Reverse Transcriptase Inhibitors 364

13.3.3 HIV Protease Inhibitors 366

13.3.4 New Research Areas 371

13.4 Antivirals for Influenza Virus 373

13.4.1 Introduction 373

13.4.2 M2 Ion Channel Inhibitors 373

13.4.3 Neuraminidase Inhibitors 375

13.4.4 New Research Areas 379

13.5 Problems 379

References 380

本章重点内容 381

14 Antifungal Agents 383

14.1 Introduction 383

14.1.1 Fungi 383

14.1.2 Fungal infections 384

14.2 Current Antifungal Agents 385

14.2.1 General 385

14.2.2 The Mechanism of Action of Major Antifungal Agents 386

14.3 Typical Antifungal Drugs in Clinical Use 390

14.3.1 Azoles Antifungal Drugs 390

14.3.2 Allyamines 398

14.4 Antifungal Drug Discovery and Development:New Modes of Action 400

14.4.1 Overview 400

14.4.2 Emerging Targets for The Development of Novel Antifungal Therapeutics 401

14.5 Problems 403

本章重点内容 404

15 Antibacterials 406

15.1 Introduction 406

15.2 β-lactam 408

15.2.1 History and Overview 408

15.2.2 Mode of Action 410

15.2.3 Mechanisms of Resistance 413

15.2.4 Major Drug Classes 414

15.3 Macrolide 419

15.3.1 Introduction 419

15.3.2 Major Classes of Macrolides 420

15.4 Tetracyclines 425

15.4.1 Introduction 425

15.4.2 SAR of Tetracyclines 425

15.4.3 Mechanism of Action 426

15.5 Aminoglycosides 427

15.6 Quinolones 430

15.6.1 Overview of Quinolones 430

15.6.2 Mechanism of Antibacterial Action 432

15.6.3 SAR and STR of Quinolones 432

15.6.4 Antibacterial Resistance Mechanisms 433

15.7 Antimycobacterial Agents 435

15.7.1 Introduction 435

15.7.2 Rifamycin 436

15.7.3 Isoniazid 436

15.8 Resistance and Challenge 438

15.9 Problems 439

本章重点内容 440

16 Antiparasitic 443

16.1 Introduction 443

16.2 Representative Diseases 445

16.2.1 Chagas Disease 445

16.2.2 Leishmaniasis 445

16.2.3 Malaria 446

16.3 Antimalarias 447

16.3.1 Quinolines 449

16.3.2 Artemisinin and its Analogs 453

16.4 Questions 457

References 457

本章重点内容 458

17 Inflammatory Diseases and Nonsteroidal Anti-inflammatory Drugs(NSAIDs) 460

17.1 Introduction[1-3] 460

17.1.1 Arthritis 461

17.1.2 Arachidonic Acid Cascade 461

17.1.3 Phospholipase A2(PLA2) 464

17.1.4 Cyclooxygenase(COX) 465

17.1.5 Lipoxygenase(LOX) 466

17.2 Current Treatment for Arthritis 466

17.2.1 Steroids(brief introduction) 466

17.2.2 Nonsteroidal Anti-inflammatory Drugs(NSAIDs) 466

17.3 Typical Nonsteroidal Anti-inflammatory Drugs in Clinical Use 477

17.4 New Research Areas 487

17.4.1 Dual COX-LOX Inhibitors 487

17.4.2 Disease-modifying Anti-rheumatic Drugs 487

17.4.3 Structure-modifying Anti-inflammatory Drugs 488

17.5 Conclusions and Future Directions 490

17.6 Problems 490

References 491

本章重点内容 492