Progress in Medicinal Chemistry (eBook)

Cover 1
Preface 6
Contents 8
List of Contributors 10
Finding Protein Kinase Hits using Structural Information 14
Introduction 15
Screening by X-ray Crystallography 17
Screening by NMR 28
Fundamentals of NMR Spectroscopy 29
Using Chemical Shift Changes 29
Nuclear-Spin Relaxation 30
Nuclear Overhauser Effects 30
Exchange Phenomena 31
Applications of NMR in Screening 31
Target-Based Screening 31
Ligand-Based Screening 32
Examples of NMR Methods for Discovering Kinase Inhibitors 33
The Shapes Strategy 33
NMR Screening by Waterlogsy Method 36
NMR Screening of Protein Kinases by ATP–STD Method 37
NMR Backbone Assignment of a Kinase 38
Designing Novel Kinase Inhibitors from the NMR-Based Screening of Fragments 40
Design of Libraries for use in NMR Screening 43
In Silico Methods 44
Receptor-Based Screening 45
Compound Database and Receptor Preparation 46
Protein–Ligand Docking 47
Scoring Functions 49
Development and Evaluation of Docking and Scoring 50
Virtual Screening and Protein Kinases 54
Faults and Fixes for Virtual Screening 57
Consensus Scoring 57
Knowledge-Based Screening 58
Protein Flexibility and Induced Fit 61
High Throughput Docking as a Virtual Screening Tool 63
Alternatives to High Throughput Docking 64
Comparative Homology Modelling 66
De Novo Design 68
Summary 71
References 72
Blunting the Swiss Army Knife of Hepatitis C Virus: Inhibitors of NS3/4A Protease* 78
Hepatitis C Infection 79
Introduction 79
The Hepatitis C Virus 80
Current Therapies for the Treatment of HCV Infections 82
The HCV NS3/4A Protease 83
Tools to Study NS3/4A Protease Inhibitors 86
Enzymatic Assays 86
Viral Replication 87
Cell culture models 87
The replicon 88
Animal models 89
Resistance studies 90
Inhibitors of the NS3/4A Serine Protease 91
Non-Covalent Peptidic Inhibitors 91
Carboxylic acid containing inhibitors 92
BILN 2061 96
Phenethyl amide containing inhibitors 98
Non-covalent aza-peptide inhibitors 99
C-terminal acyl sulfonamide containing inhibitors 100
Prime-side inhibitors 102
Covalent Reversible Peptidic Inhibitors 103
Non-Peptidic Inhibitors 110
Summary and Outlook 111
References 113
Peptide Deformylase Inhibitors 122
Introduction 123
Peptide Deformylase as a Novel Antibacterial Target 123
Function 124
Essentiality 125
Spectrum 125
Selectivity 126
Protein Structure of Peptide Deformylases 126
Three-Dimensional Structure 126
Metal-Binding Site 127
Fe2+-PDF 127
Comparison with Other Metalloproteases 128
Substrate-Binding Pockets 128
S1' pocket 129
S2' pocket 129
S3' pocket 130
Design and SAR of Peptide Deformylase Inhibitors 130
Early Substrate-Based Inhibitors 130
SAR from substrate specificity studies 130
Thiols 131
H-phosphonates 133
Aldehydes 133
Pseudopeptidic Hydroxamic Acids and N-Formyl-N-Hydroxylamines 134
Actinonin 134
P2' t-Butyl containing inhibitors 135
P2' Proline-derived inhibitors 137
ß-Aminohydroxamic acids 139
Non-Peptidic Templates 140
Thyropropic acid analogues 141
Biaryl acids 141
ß-Sulfonyl- and ß-sulfinylhydroxamic acids 142
Benzamides and aryl ethers 143
Bicyclic hydroxamic acids 143
Isoxazoles 145
Macrocycles 145
Sch 382582 and Sch 382583 146
Other patent activity 147
Clinical Candidates 148
BB-83698 148
LBM-415 149
Summary and Perspectives 149
Acknowledgements 150
References 151
Clinically Useful Vanilloid Receptor TRPV1 Antagonists: Just around the Corner (or too Early to Tell)? 158
Introduction 159
The Theory: Can TRPV1 Antagonists Function as Clinically useful Drugs? (The Pros and The Cons) 160
TRPV1 Antagonists: an Overview of Chemistry and Pharmacology 164
Iodinated Capsaicinoids and Resiniferonoids 165
4-Heteroarylpiperazine-1-Carboxyarylamides 167
BCTC 167
Johnson & Johnson piperazine carboxamides
N-Arylcinnamides 171
AMG 9810 171
SB-366791 172
N-(Aza)naphthyl-N'-aryl(benzyl)ureas 173
Abbott lead 173
Johnson & Johnson leads
N-Aryl-N'-Alkylaminocarbonyl Ethylendiamines 174
N, N'-Dibenzylthioureas 175
Miscellaneous Natural and Endogenous Products 176
Miscellaneous Structures from the Proprietary Literature 177
Potential Clinical Indications for TRPV1 Blockade 183
Chronic, Intractable Pain (Neuropathic, Cancer, AIDS, etc.) Vulvodynia
Faecal and Urinary Incontinence 183
Inflammatory Bowel Disease and Motility Disorders 184
Chronic Arthritis 184
Acute Pancreatitis 184
Human Hair Growth Control (Alopecia) and Dermatologic Disorders 184
Antitussive Activity 185
Immunoregulation 185
Concluding Remarks: TRPV1 Agonists Versus Antagonists – Which way to Go? 185
References 186
Recent Medicinal Chemistry of the Histamine H3 Receptor 194
Introduction 194
New Biological Insights 195
Clinical Applications 201
Histamine H3 Receptor Antagonists/Inverse Agonists 201
Imidazole-Based Ligands 201
Non-Imidazole-Based Ligands 203
Ligands with Multiple Modes of Action 210
Histamine H3 Receptor Agonists 211
Molecular Modelling 212
Conclusion 212
References 213
Recent Progress in Cannabinoid Research 220
Introduction 221
Cannabinoid Receptors and Endocannabinoids 221
Anandamide Transport Inhibitors 223
The Hydrophobic Chain 224
The Carboxamide/Carboxylate Group 224
The Polar Head Group 224
Fatty Amide Acid Hydrolase Inhibitors 225
Organosulfonate and Organophosphonate Analogues 226
Trifluoromethylketones 228
a-Ketoheterocycles 229
Carbamates 230
Other Structures 232
Cannabinoid Receptor Agonists 233
Classical Cannabinoids 233
C3 Side-chain modifications 235
C9 Substituent modifications 242
C1 modifications 244
Core modifications 245
Cannabidiol Derivatives (Resorcinols) 246
Non-Classical Cannabinoids 248
Endocannabinoid Derivatives 250
Anandamide derivatives 250
The fatty acid chain 251
The carboxamide group 255
The polar head group 256
2-Arachidonylglycerol 259
Noladin ether 259
Indole and its Derivatives 260
Indoles 260
Pyrrole and its derivatives 266
Indenes 268
Other structures 271
CB2 Agonists 272
CB2 Selective Classical Cannabinoids 273
Indoles and Indazoles 275
Resorcinol Derivatives 279
Benzo[c]Chromen-6-One Derivatives 281
Other Heterocyclic CB2 Agonists 282
Therapeutic Applications of Cannabinoid Agonists 283
CB1 Receptor Antagonists 285
1,5-Diaryl-Pyrazoles 286
4,5-Dihydro-1H-Pyrazole Derivatives 295
Imidazole-, Thiazole-, Pyrrole- and Triazole-Based CB1 Receptor Antagonists 298
Pyridine-, Phenyl-, Pyrimidine- and Pyrazole-Based CB1 Receptor Antagonists 308
Azetidine-Based CB1 Receptor Antagonists 314
Substituted Amide-Based CB1 Receptor Antagonists 316
Hydantoin-Based CB1 Receptor Analogues 317
Recent CB1 Receptor Antagonists 320
Therapeutic Applications of CB1 Receptor Antagonists 321
CB2 Receptor Antagonists 323
Summary and Future Prospects 326
References 326
Oxytocin Antagonists as Potential Therapeutic Agents for the Treatment of Preterm Labour 344
Introduction 345
Epidemiology and the Impact of Preterm Labour 345
The Anatomy of the Uterus 346
Treatment of Preterm Labour 346
The Role of Oxytocin in Labour 347
Regulation of Oxytocin during Labour 347
Regulation of the Oxytocin Receptor 348
Experiences with Oxytocin Antagonists 348
Selective OT or Mixed OT/V1A Blockade? 349
Extra Uterine Roles of Oxytocin 350
Methods used to Measure Oxytocin Antagonist Activity 350
Competition Binding 350
Functional Responses Quantified by Second Messenger Measurement 351
Functional Responses Quantified by Smooth Muscle Contraction 352
Peptide Antagonists 352
Atosiban 361
Non-Peptide Antagonists 362
Oxytocin Agonists 375
Structural Studies of Oxytocin Receptor 376
Conclusion 380
References 380
Subject Index 388
Author Index (Vols. 1–44) 392
Subject Index (Vols. 1–44) 398