An introduction to medicinal chemistry:
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| Format: | Buch |
| Sprache: | English |
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Oxford
Oxford University Press
[2017]
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| Ausgabe: | Sixth edition |
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| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | xxxi, 877 Seiten Illustrationen, Diagramme |
| ISBN: | 9780198749691 |
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| 100 | 1 | |a Patrick, Graham L. |e Verfasser |0 (DE-588)108943457X |4 aut | |
| 245 | 1 | 0 | |a An introduction to medicinal chemistry |c Graham L. Patrick |
| 250 | |a Sixth edition | ||
| 264 | 1 | |a Oxford |b Oxford University Press |c [2017] | |
| 264 | 4 | |c © 2017 | |
| 300 | |a xxxi, 877 Seiten |b Illustrationen, Diagramme | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
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Datensatz im Suchindex
| _version_ | 1804177425799577600 |
|---|---|
| adam_text | Titel: An introduction to medicinal chemistry
Autor: Patrick, Graham L
Jahr: 2017
Detailed contents
List of boxes xxvi
Acronyms and abbreviations xxviii
1 Drugs and drug targets: an overview 1
1.1 What is a drug? 1
1.2 Drug targets 3
1.2.1 Cell structure 3
1.2.2 Drug targets at the molecular level 4
1.3 Intermolecular bonding forces 5
1.3.1 Electrostatic or ionic bonds 5
Hydrogen bonds 6
Van der Waals interactions 8
Dipole-dipole and ion-dipole interactions 8
Repulsive interactions 9
3.5
1.3.2
1.3.3
1.3.4
1.3.5
1.3.6
The role of water and hydrophobic interactions 10
1.4 Pharmacokinetic issues and medicines
1.5 Classification of drugs
1.5 Naming of drugs and medicines
PART A Drug targets
2 Protein structure and function
2.1 The primary structure of proteins
2.2 The secondary structure of proteins
2.2.1 The a-helix
2.2.2 The P-pleated sheet
2.2.3 The p-turn
2.3 The tertiary structure of proteins
2.3.1 Covalent bonds: disulphide links
2.3.2 Ionic or electrostatic bonds
2.3.3 Hydrogen bonds
2.3.4 Van der Waals and hydrophobic interactions
2.3.5 Relative importance of bonding interactions
2.3.6 Role of the planar peptide bond
2.4 The quaternary structure of proteins
2.5 Translation and post-translational modifications
2.6 Proteomics
2.7 Protein function
2.7.1 Structural proteins
2.7.2 Transport proteins
2.7.3 Enzymes and receptors
2.7.4 Miscellaneous proteins and protein-protein
interactions
3 Enzymes: structure and function
3.1 Enzymes as catalysts
3.2 How do enzymes catalyse reactions?
3.3 The active site of an enzyme
3.4 Substrate binding at an active site
11
11
12
The catalytic role of enzymes
32
3.5.1
Binding interactions
32
3.5.2
Acid-base catalysis
33
3.5.3
Nucleophilic groups
34
3.5.4
Stabilization of the transition state
35
3.5.5
Cofactors
35
3.5.6
Naming and classification of enzymes
37
3.5.7
Genetic polymorphism and enzymes
37
Regulation of enzymes
38
Isozymes
40
Enzyme kinetics
41
3.8.1
The Michaelis-Menten equation
41
3.8.2
Lineweaver-Burk plots
42
3.6
3.7
3.8
Box 3.1 The external control of enzymes by
nitric oxide
4 Receptors: structure and function
4.1 Role of the receptor
4.2 Neurotransmitters and hormones
4.3 Receptor types and subtypes
4.4 Receptor activation
39
44
44
44
47
47
17
4.5
How does the binding site change shape?
47
17
4.6
Ion channel receptors
49
18
4.6.1
General principles
49
18
4.6.2
Structure
50
18
4.6.3
Gating
51
18
4.6.4
Ligand-gated and voltage-gated ion channels
51
19
4.7
G-protein-coupled receptors
52
21
4.7.1
General principles
52
21
4.7.2
Structure
53
21
4.7.3
The rhodopsin-like family of
22
G-protein-coupled receptors
53
23
4.7.4
Dimerization of G-coupled receptors
55
23
4.8
Kinase
receptors
55
23
4.8.1
General principles
55
25
4.8.2
Structure of tyrosine kinase receptors
56
26
4.8.3
Activation mechanism for tyrosine
26
kinase receptors
56
4.8.4
Tyrosine kinase receptors as targets in
26
drug discovery
57
27
4.8.4.1 The ErbB family of tyrosine
27
kinase receptors
4.8.4.2 Vascular endothelial growth
57
28
factor receptors
58
30
4.8.4.3 Platelet-derived growth factor
receptor
58
30
4.8.4.4 Stem cell growth factor receptor
58
31
4.8.4.5 Anaplastic lymphoma kinase (ALK)
58
31
4.8.4.6 The RET receptor
58
4.8.4.7 Hepatocyte growth factor receptor or
32
c-MET receptor
58
xiv Detailed contents
4.9 Intracellular receptors
4.10 Regulation of receptor activity
4.11 Genetic polymorphism and receptors
5 Receptors and signal transduction
5.1
59
59
60
61
PART B Pharmacodynamics and
pharmacokinetics
7 Enzymes as drug targets
7.1 Inhibitors acting at the active site of
5.2
5.3
5.4
6 Nucleic acids: structure and function
6.1 Structure of DNA
6.1.1 The primary structure of DNA
6.1.2 The secondary structure of DNA
6.1.3 The tertiary structure of DNA
6.1.4 Chromatins
6.1.5 Genetic polymorphism and
personalized medicine
6.2 Ribonucleic acid and protein synthesis
6.2.1 Structure of RNA
6.2.2 Transcription and translation
6.2.3 Small nuclear RNA
6.2.4 The regulatory role of RNA
6.3 Genetic illnesses
6.4 Molecular biology and genetic engineering
77
77
77
77
80
82
82
82
82
83
85
85
85
87
8.2.1 Binding groups
8.2.2 Position of the binding groups
8.2.3 Size and shape
8.2.4 Other design strategies
8.2.5 Pharmacodynamics and pharmacokinetics
8.2.6 Examples of agonists
8.2.7 Allosteric modulators
8.3 The design of antagonists :
8.3.1 Antagonists acting at the binding site
8.3.2 Antagonists acting outwith the ?
binding site b.
8.4 Partial agonists ¦* .
8.5 Inverse agonists
8.6 Desensitization and sensitization
8.7 Tolerance and dependence
93
Signal transduction pathways for
an enzyme . ¦: -
93
G-protein-coupled receptors
61
7.1.1 Reversible inhibitors
93
5.1.1 Interaction of the receptor-ligand , ,
61
7.1.2 Irreversible inhibitors •
94
complex with G-proteins
96
5.1.2 Signal transduction pathways involving
62
7.2
Inhibitors acting at allosteric binding sites
the a-subunit
7.3
Uncompetitive and non-competitive
Signal transduction involving G-proteins
inhibitors
96
and adenylate cyclase
63
7.4
Transition-state analogues: renin inhibitors
97
5.2.1 Activation of adenylate cyclase by
63
7.5
Suicide substrates
98
the as-subunit
5.2.2 Activation of protein kinase A
64
7.6
Isozyme selectivity of inhibitors
99
5.2.3 The G(-protein
65
7.7
Medicinal uses of enzyme inhibitors
99
5.2.4 General points about the signalling
7.7.1 Enzyme inhibitors used against
cascade involving cyclic AMP
66
microorganisms
99
5.2.5 The role of the fty-dimer
66
7.7.2 Enzyme inhibitors used against viruses
101
5.2.6 Phosphorylation
66
f r
7.7.3 Enzyme inhibitors used against the
Signal transduction involving G-proteins
body s own enzymes
101
and phospholipase Cp
68
-
7.7.4 Enzyme modulators
103
5.3.1 G-protein effect on phospholipase Cp
68
7.8
Enzyme kinetics
104
5.3.2 Action of the secondary messenger:
7.8.1 Lineweaver-Burk plots
104
diacylglycerol
68
7.8.2 Comparison of inhibitors
106
5.3.3 Action of the secondary messenger:
94
inositol triphosphate
68
Box /.l A cure for antifreeze poisoning
5.3.4 Resynthesis of phosphatidylinositol
Box 7.2 Irreversible inhibition for the treatment
diphosphate
70
of obesity
96
Signal transduction involving kinase receptors
70
Box 7.3 Suicide substrates
100
5.4.1 Activation of signalling proteins and enzymes
70
Box 7.4 Designing drugs to be isozyme selective
101
5.4.2 The MAPK signal transduction pathway
71
102
5.4.3 Activation of guanylate cyclase by
Box 7.5 Action of toxins on enzymes
kinase receptors
71
Box 7.6 Kinase inhibitors
104
5.4.4 The JAK-STAT signal transduction pathway
72
5.4.5 The PI3K/Akt/mTOR signal transduction
pathway
73
8 Receptors as drug targets
109
8.1
Introduction
109
The hedgehog signalling pathway
74
8.2
The design of agonists
109
Detailed contents xv
8.8 Receptor types and subtypes 122
8.9 Affinity, efficacy, and potency 124
Box 8.1 An unexpected agonist 113
Box 8.2 Estradiol and the estrogen receptor 116
9 Nucleic acids as drug targets 128
9.1 Intercalating drugs acting
on DNA 128
9.2 Topoisomerase poisons:
non-intercalating 129
9.3 Alkylating and metallating agents 131
9.3.1 Nitrogen mustards 132
9.3.2 Nitrosoureas 132
9.3.3 Busulfan 132
9.3.4 Cisplatin 133
9.3.5 Dacarbazine and procarbazine 134
9.3.6 Mitomycin C 135
9.4 Chain cutters 136
9.5 Chain terminators 137
9.6 Control of gene transcription 138
9.7 Agents that act on RNA 139
9.7.1 Agents that bind to ribosomes 139
9.7.2 Antisense therapy 139
10 Miscellaneous drug targets 144
10.1 Transport proteins as drug targets 144
10.2 Structural proteins as drug targets 144
10.2.1 Viral structural proteins as drug targets 144
10.2.2 Tubulin as a drug target 145
10.2.2.1 Agents which inhibit tubulin
polymerization 145
10.2.2.2 Agents which inhibit tubulin
depolymerization 146
10.3 Biosynthetic building blocks as drug targets 147
10.4 Biosynthetic processes as drug targets:
chain terminators 148
10.5 Protein-protein interactions 148
10.6 Lipids as a drug target 152
10.6.1 Tunnelling molecules 152
10.6.2 Ion carriers 155
10.6.3 Tethers and anchors 156
10.7 Carbohydrates as drug targets 157
10.7.1 Glycomics 157
10.7.2 Antigens and antibodies 158
10.7.3 Cyclodextrins 160
Box 10.1 Antidepressant drugs acting on transport
proteins 145
Box 10.2 Targeting transcription factor-coactivator
interactions 149
Box 10.3 Cyclodextrins as drug scavengers 159
11 Pharmacokinetics and related topics 162
11.1 The three phases of drug action 162
11.2 A typical journey for an orally active drug 162
11.3 Drug absorption 163
11.4 Drug distribution 165
11.4.1 Distribution round the blood supply 165
11.4.2 Distribution to tissues 165
11.4.3 Distribution to cells 165
11.4.4 Other distribution factors 165
11.4.5 Blood-brain barrier 166
11.4.6 Placental barrier 166
11.4.7 Drug-drug interactions 166
11.5 Drug metabolism 167
11.5.1 Phase I and phase II metabolism 167
11.5.2 Phase I transformations catalysed by
cytochrome P450 enzymes 167
11.5.3 Phase I transformations catalysed by
flavin-containing monooxygenases 170
11.5.4 Phase I transformations catalysed by
other enzymes 170
11.5.5 Phase II transformations 171
11.5.6 Metabolic stability 172
11.5.7 The first pass effect 176
11.6 Drug excretion 176
11.7 Drug administration 177
11.7.1 Oral administration 178
11.7.2 Absorption through mucous membranes 178
11.7.3 Rectal administration 178
11.7.4 Topical administration 178
11.7.5 Inhalation 179
11.7.6 Injection 179
11.7.7 Implants 180
11.8 Drug dosing 180
11.8.1 Drug half-life 181
11.8.2 Steady state concentration 181
11.8.3 Drug tolerance 182
11.8.4 Bioavailability 182
11.9 Formulation 182
11.10 Drug delivery 183
Box 11.1 Metabolism of an antiviral agent 175
Case study 1: Statins 187
¦ CS1.1 Cholesterol and coronary heart disease 187
¦ CS1.2 The target enzyme 188
¦ CS1.3 The discovery of statins 190
¦ CS1.4 Mechanism of action for statins:
pharmacodynamics 192
¦ CS1.5 Binding interactions of statins 192
¦ CS1.6 Other mechanisms of action for statins 193
¦ CS1.7 Other targets for cholesterol-lowering
drugs 194
xvi Detailed contents
PART C Drug discovery, design, and
development
12 Drug discovery: finding a lead
12.1 Choosing a disease
12.2 Choosing a drug target
12.2.1 Drug targets
12.2.2 Discovering drug targets
197
197
197
197
197
199
12.2.3 Target specificity and selectivity between
species
12.2.4 Target specificity and selectivity within
the body 199
12.2.5 Targeting drugs to specific organs and tissues 200
12.2.6 Pitfalls 200
12.2.7 Multi-target drugs . , 201
12.3 Identifying a bioassay 203
12.3.1 Choice of bioassay 203
12.3.2 In vitro tests 203
12.3.3 In vivo tests 203
12.3.4 Test validity 204
12.3.5 High-throughput screening 204
12.3.6 Screening by NMR 205
12.3.7 Affinity screening 205
12.3.8 Surface plasmon resonance 205
12.3.9 Scintillation proximity assay 206
12.3.10 Isothermal titration calorimetry 206
12.3.11 Virtual screening 207
12.4 Finding a lead compound 207
12.4.1 Screening of natural products 207
12.4.1.1 The plant kingdom 207
12.4.1.2 Microorganisms 208
12.4.1.3 Marine sources 209
12.4.1.4 Animal sources 209
12.4.1.5 Venoms and toxins 210
12.4.2 Medical folklore 210
12.4.3 Screening synthetic compound libraries 210
12.4.4 Existing drugs 211
12.4.4.1 Me too and me better drugs 211
12.4.4.2 Enhancing a side effect 211
12.4.5 Starting from the natural ligand or modulator 214
12.4.5.1 Natural ligands for receptors 214
12.4.5.2 Natural substrates for enzymes 214
12.4.5.3 Enzyme products as lead
compounds 214
12.4.5.4 Natural modulators as lead
compounds 215
12.4.6 Combinatorial and parallel synthesis 215
12.4.7 Computer-aided design of lead compounds 215
12.4.8 Serendipity and the prepared mind 215
12.4.9 Computerized searching of structural
databases 217
12.4.10 Fragment-based lead discovery 217
12.4.11 Properties of lead compounds 219
12.5 Isolation and purification 220
12.6 Structure determination 220
12.7 Herbal medicine 220
224
225
226
Box 12.1 Recently discovered targets: the caspases 198
Box 12.2 Pitfalls in choosing particular targets 200
Box 12.3 Early tests for potential toxicity 201
Box 12.4 Selective optimization of side activities (SOSA) 213
Box 12.5 Natural ligands as lead compounds 214
Box 12.6 Examples of serendipity 216
Box 12.7 The use of NMR spectroscopy in finding
lead compounds 217
Box 12.8 Click chemistry in situ 219
13 Drug design: optimizing target interactions 223
13.1 Structure-activity relationships 223
13.1.1 Binding role of alcohols and phenols
13.1.2 Binding role of aromatic rings
13.1.3 Binding role of alkenes
13.1.4 Tbe binding role of ketones and
aldehydes 226
13.1.5 Binding role of amines • 226
13.1.6 Binding role of amides 228
13.1.7 Binding role of quaternary
ammonium salts 229
13.1.8 Binding role of carboxylic acids 229
13.1.9 Binding role of esters 230
13.1.10 Binding role of alkyl and aryl halides 230
13.1.11 Binding role of thiols and ethers 231
13.1.12 Binding role of other functional groups 231
13.1.13 Binding role of alkyl groups and the
carbon skeleton 231
13.1.14 Binding role of heterocycles 232
13.1.15 Isosteres 233
13.1.16 Testing procedures 234
13.1.17 SAR in drug optimization 234
13.2 Identification of a pharmacophore 235
13.3 Drug optimization: strategies in drug design 236
13.3.1 Variation of substituents 236
13.3.1.1 Alkyl substituents 236
13.3.1.2 Substituents on aromatic or
heteroaromatic rings 237
13.3.1.3 Synergistic effects 238
13.3.2 Extension of the structure 239
13.3.3 Chain extension/contraction 239
13.3.4 Ring expansion/contraction 239
13.3.5 Ring variations 241
13.3.6 Ring fusions 242
13.3.7 Isosteres and bio-isosteres 243
13.3.8 Simplification of the structure 244
13.3.9 Rigidification of the structure 247
13.3.10 Conformational blockers 248
13.3.11 Structure-based drug design and
molecular modelling 248
13.3.12 Drug design by NMR spectroscopy 250
13.3.13 The elements of luck and inspiration 250
13.3.14 Designing drugs to interact with more
than one target 252
13.3.14.1 Agents designed from known drugs 252
13.3.14.2 Agents designed from
non-selective lead compounds 253
Detailed contents xvii
Box 13.1 Converting an enzyme substrate to an
inhibitor by extension tactics 240
Box 13.2 Simplification 245
Box 13.3 Rigid if ication tactics in drug design 249
Box 13.4 The structure-based drug design of crizotinib 251
14 Drug design: optimizing access to
the target 256
14.1 Optimizing hydrophilic/hydrophobic properties 256
14.1.1 Masking polar functional groups to
decrease polarity 257
14.1.2 Adding or removing polar functional
groups to vary polarity 257
14.1.3 Varying hydrophobic substituents to
vary polarity 257
14.1.4 Variation of N-alkyl substituents to vary piCa 258
14.1.5 Variation of aromatic substituents to vary pKa 258
14.1.6 Bio-isosteres for polar groups 258
14.2 Making drugs more resistant to chemical
and enzymatic degradation 259
14.2.1 Steric shields 259
14.2.2 Electronic effects of bio-isosteres 259
14.2.3 Steric and electronic modifications 260
14.2.4 Metabolic blockers 260
14.2.5 Removal or replacement of susceptible
metabolic groups 261
14.2.6 Group shifts 261
14.2.7 Ring variation and ring substituents 262
14.3 Making drugs less resistant to drug metabolism 263
14.3.1 Introducing metabolically susceptible groups 263
14.3.2 Self-destruct drugs 263
14.4 Targeting drugs 264
14.4.1 Targeting tumour cells: search and
destroy drugs 264
14.4.2 Targeting gastrointestinal infections 265
14.4.3 Targeting peripheral regions rather
than the central nervous system 265
14.4.4 Targeting with membrane tethers 265
14.5 Reducing toxicity 266
14.6 Prodrugs 266
14.6.1 Prodrugs to improve membrane permeability 267
14.6.1.1 Esters as prodrugs 267
14.6.1.2 N-Methylated prodrugs 268
14.6.1.3 Trojan horse approach for transport
proteins 268
14.6.2 Prodrugs to prolong drug activity 269
14.6.3 Prodrugs masking drug toxicity and side
effects 270
14.6.4 Prodrugs to lower water solubility 270
14.6.5 Prodrugs to improve water solubility 270
14.6.6 Prodrugs used in the targeting of drugs 271
14.6.7 Prodrugs to increase chemical stability 272
14.6.8 Prodrugs activated by external influence
{sleeping agents) 273
14.7 Drug alliances 273
14.7.1 Sentry drugs 273
14.7.2 Localizing a drugs area of activity 274
14.7.3 Increasing absorption 274
14.8 Endogenous compounds as drugs 274
14.8.1 Neurotransmitters 274
14.8.2 Natural hormones, peptides, and
proteins as drugs 275
14.8.3 Antibodies as drugs 276
14.9 Peptides and peptidomimetics in drug design 277
14.9.1 Peptidomimetics 278
14.9.2 Peptide drugs 280
14.10 Oligonucleotides as drugs 280
Box 14.1 The use of bio-isosteres to increase absorption 259
Box 14.2 Shortening the lifetime of a drug 264
Box 14.3 Identifying and replacing potentially
toxic groups 267
Box 14.4 Varying esters in prodrugs 269
Box 14.5 Prodrugs masking toxicity and side effects 271
Box 14.6 Prodrugs to improve water solubility 272
15 Getting the drug to market 284
15.1 Preclinical and clinical trials 284
15.1.1 Toxicity testing 284
15.1.2 Drug metabolism studies 285
15.1.3 Pharmacology, formulation, and stability tests 287
15.1.4 Clinical trials 287
15.1.4.1 Phase I studies 288
15.1.4.2 Phase II studies 288
15.1.4.3 Phase III studies 289
15.1.4.4 Phase IV studies 289
15.1.4.5 Ethical issues 290
15.2 Patenting and regulatory affairs 291
15.2.1 Patents 291
15.2.2 Regulatory affairs 293
15.2.2.1 The regulatory process 293
15.2.2.2 Fast tracking and orphan drugs 294
15.2.2.3 Good laboratory, manufacturing,
and clinical practice 294
15.2.2.4 Analysis of cost versus benefits 295
15.3 Chemical and process development 295
15.3.1 Chemical development 295
15.3.2 Process development 297
15.3.3 Choice of drug candidate 299
15.3.4 Natural products 299
Box 15.1 Drug metabolism studies and drug design 286
Box 15.2 Synthesis of ebalzotan 296
Box 15.3 Synthesis of ICI D7114 297
Case study 2: The design of ACE inhibitors 302
BoxCS2.1 Synthesis of captopril and enalaprilat 307
Case study 3: Artemisinin and related antimalarial drugs 309
¦ CS3.1 Introduction 309
¦ CS3.2 Artemisinin 309
¦ CS3.3 Structure and synthesis of artemisinin 310
xviii Detailed contents
¦ C$3.4 Structure-activity relationships
¦ C$3.5 Mechanism of action
¦ CS3.6 Drug design and development
Box CS3.1 Clinical properties of artemisinin and -
analogues
Case study 4: The design of oxamniquine
¦ CS4.1 Introduction
¦ CS4.2 From lucanthone to oxamniquine
¦ CS4.3 Mechanism of action
¦ CS4.4 Other agents
Box CS4.1 Synthesis of oxamniquine
PART D Tools of the trade
16 Combinatorial and parallel synthesis
16.1 Combinatorial and parallel synthesis in ¦
medicinal chemistry projects
16.2 Solid-phase techniques
16.2.1 The solid support
16.2.2 The anchor/linker
16.2.3 Examples of solid-phase syntheses
16.3 Planning and designing a compound library
16.3.1 Spider-like scaffolds
16.3.2 Designing drug-like molecules
16.3.3 Synthesis of scaffolds
16.3.4 Substituent variation
16.3.5 Designing compound libraries for
lead optimization
16.3.6 Computer-designed libraries
16.4 Testing for activity
16.4.1 High-throughput screening
16.4.2 Screening on bead or off bead
16.5 Parallel synthesis
16.5.1 Solid-phase extraction
16.5.2 The use of resins in solution-phase organic
synthesis (SPOS)
16.5.3 Reagents attached to solid support:
catch and release
16.5.4 Microwave technology
16.5.5 Microfluidics in parallel synthesis
16.6 Combinatorial synthesis
16.6.1 The mix and split method in combinatorial
synthesis
16.6.2 Structure determination of the active
compound(s)
16.6.2.1 Tagging
16.6.2.2 Photolithography
16.6.3 Dynamic combinatorial synthesis
Box 16.1 Examples of scaffolds
Box 16.2 Dynamic combinatorial synthesis of
vancomycin dimers
310
311
313
313
315
315
315
319
319
320
325
325
326
326
327
329
330
330
330
331
331
331
332
333
333
333
334
334
336
336
337
337
340
340
341
341
343
343
332
346
17 Computers in medicinal chemistry
17.1 Molecular and quantum mechanics
17.1.1 Molecular mechanics
17.1.2 Quantum mechanics
17.1.3 Choice of method :
17.2 Drawing chemical structures
17.3 3D structures
17.4 Energy minimization
17.5 Viewing 3D molecules
17.6 Molecular dimensions
17.7 Molecular properties
17.7.1 Partial charges
17.7.2 Molecular electrostatic potentials
17.7.3 Molecular orbitals
17.7.4 Spectroscopic transitions
17.7.5 The use of grids in measuring molecular
properties
17.8 Conformational analysis
17.8.1 Local and global energy minima t
17.8.2 Molecular dynamics
17.8.3 Stepwise bond rotation
17.8.4 Monte Carlo and the Metropolis method
17.8.5 Genetic and evolutionary algorithms
17.9 Structure comparisons and overlays
17.10 Identifying the active conformation
17.10.1 X-ray crystallography
17.10.2 Comparison of rigid and non-rigid ligands 365
17.11 3D pharmacophore identification 366
17.11.1 X-ray crystallography 367
17.11.2 Structural comparison of active compounds 367
17.11.3 Automatic identification of
pharmacophores 367
17.12 Docking procedures 368
17.12.1 Manual docking 368
17.12.2 Automatic docking 369
17.12.3 Defining the molecular surface of a
binding site 369
17.12.4 Rigid docking by shape complementarity 370
17.12.5 The use of grids in docking programs 372
17.12.6 Rigid docking by matching hydrogen
bonding groups 373
17.12.7 Rigid docking of flexible ligands:
the FLOG program 373
17.12.8 Docking of flexible ligands: anchor and
grow programs 373
17.12.8.1 Directed Dock and Dock 4.0 374
17.12.8.2 FlexX 374
17.12.8.3 The Hammerhead program 376
17.12.9 Docking of flexible ligands: simulated
annealing and genetic algorithms 377
17.13 Automated screening of databases for
lead compounds and drug design 378
17.14 Protein mapping 373
17.14.1 Constructing a model protein:
homology modelling 378
349
349
349
349
350
350
350
351
351
353
353
353
354
355
355
356
358
358
358
359
360
362
363
364
364
Detailed contents xix
17.14.2 Constructing a binding site:
hypothetical pseudoreceptors 380
17.15 De novo drug design 381
17.15.1 General principles of de novo drug design 381
17.15.2 Automated de novo drug design 383
17.15.2.1 LUDI 383
17.15.2.2 SPROUT 387
17.15.2.3 LEGEND 389
17.15.2.4 GROW, ALLEGRO W,
and SYNOPSIS 390
17.16 Planning compound libraries 390
17.17 Database handling 392
Box 17.1 Energy minimizing apomorphine 352
Box 17.2 Study of HOMO and LUMO orbitals 356
Box 17.3 Finding conformations of cyclic structures
by molecular dynamics 359
Box 17.4 Identification of an active conformation 365
Box 17.5 Constructing a receptor map 382
Box 17.6 Designing a non-steroidal glucocorticoid agonist 391
18 Quantitative structure-activity
relationships (QSAR) 395
18.1 Graphs and equations 395
18.2 Physicochemical properties 396
18.2.1 Hydrophobicity 397
18.2.1.1 The partition coefficient (P) 397
18.2.1.2 The substituent hydrophobicity
constant (71) 398
18.2.1.3 Pversusit 399
18.2.2 Electronic effects 400
18.2.3 Steric factors 402
18.2.3.1 Taft s steric factor (Es) 403
18.2.3.2 Molar refractivity 403
18.2.3.3 Verloop steric parameter 403
18.2.4 Other physicochemical parameters 404
18.3 Hansch equation 404
18.4 The Craig plot 404
18.5 The Topliss scheme 406
18.6 Bio-isosteres 409
18.7 The Free-Wilson approach 409
18.8 Planning a QSAR study 409
18.9 Case study 410
18.10 3D QSAR 413
18.10.1 Defining steric and electrostatic fields 413
18.10.2 Relating shape and electronic distribution
to biological activity 414
18.10.3 Advantages of CoMFA over traditional QSAR 415
18.10.4 Potential problems of CoMFA 415
18.10.5 Other 3D QSAR methods 416
18.10.6 Case study: inhibitors of tubulin polymerization 416
Box 18.1 Altering log P to remove central nervous
system side effects 399
Box 18.2 Insecticidal activity of diethyl phenyl
phosphates 402
Box 18.3 Hansch equation for a series of
antimalarial compounds 405
Case study 5: Design of a thymidylate synthase inhibitor 419
PART E Selected topics in medicinal chemistry
19 Antibacterial agents 425
19.1 History of antibacterial agents 425
19.2 The bacterial cell 427
19.3 Mechanisms of antibacterial action 427
19.4 Antibacterial agents which act against cell
metabolism (antimetabolites) 428
19.4.1 Sulphonamides 428
19.4.1.1 The history of sulphonamides 428
19.4.1.2 Structure-activity relationships 428
19.4.1.3 Sulphanilamide analogues 428
19.4.1.4 Applications of sulphonamides 429
19.4.1.5 Mechanism of action 430
19.4.2 Examples of other antimetabolites 432
19.4.2.1 Trimethoprim 432
19.4.2.2 Sulphones 432
19.5 Antibacterial agents which inhibit cell wall
synthesis 433
19.5.1 Penicillins 433
19.5.1.1 History of penicillins 433
19.5.1.2 Structure of benzylpenicillin and
phenoxymethylpenicillin 434
19.5.1.3 Properties of benzylpenicillin 434
19.5.1.4 Mechanism of action for penicillin 435
19.5.1.5 Resistance to penicillin 438
19.5.1.6 Methods of synthesizing
penicillin analogues 440
19.5.1.7 Structure-activity relationships
of penicillins 441
19.5.1.8 Penicillin analogues 441
19.5.1.9 Synergism of penicillins with
other drugs 447
19.5.2 Cephalosporins 448
19.5.2.1 Cephalosporin C 448
19.5.2.2 Synthesis of cephalosporin
analogues at position 7 449
19.5.2.3 First-generation cephalosporins 450
19.5.2.4 Second-generation cephalosporins 451
19.5.2.5 Third-generation cephalosporins 452
19.5.2.6 Fourth-generation cephalosporins 452
19.5.2.7 Fifth-generation cephalosporins 453
19.5.2.8 Resistance to cephalosporins 453
19.5.3 Other p-lactam antibiotics 454
19.5.3.1 Carbapenems 454
19.5.3.2 Monobactams 455
19.5.4 (3-Lactamase inhibitors 455
19.5.4.1 Clavulanic acid 455
19.5.4.2 Penicillanic acid sulphone
derivatives 457
457
457
458
458
459
464
464
464
464
464
xx Detailed contents
19.5.4.3 Otivanic acids
19.5.4.4 Avibactam
19.5.5 Other drugs which act on bacterial cell
wall biosynthesis
19.5.5.1 D-Cycloserine and bacitracin
19.5.5.2 The glycopeptides: vancomycin
and vancomycin analogues
19.6 Antibacterial agents which act on the plasma
membrane structure
19.6.1 Valinomycin and gramicidin A
19.6.2 Polymyxin B
19.6.3 Killer nanotubes
19.6.4 Cyclic lipopeptides
19.7 Antibacterial agents which impair protein synthesis:
translation 466
19.7.1 Aminoglycosides 466
19.7.2 Tetracyclines 468
19.7.3 Chloramphenicol 472
19.7.4 Macrolides 473
19.7.5 Lincosamides 474
19.7.6 Streptogramins 475
19.7.7 Oxazolidinones • j 1 - 475
19.7.8 Pleuromutilins 476
19.8 Agents that act on nucleic acid transcription
and replication 476
19.8.1 Quinolones and fluoroquinolones 476
19.8.2 Aminoacridines 478
19.8.3 Rifamycins 479
19.8.4 Nitroimidazoles and nitrofurantoin 479
19.8.5 Inhibitors of bacterial RNA polymerase 479
19.9 Miscellaneous agents 480
19.10 Drug resistance 482
19.10.1 Drug resistance by mutation 483
19.10.2 Drug resistance by genetic transfer 483
19.10.3 Other factors affecting drug resistance 483
19.10.4 The way ahead 484
Box 19.1 Sulphonamide analogues with reduced toxicity 429
Box 19.2 Treatment of intestinal infections 430
Box 19.3 Clinical properties of benzylpenicillin and
phenoxymethylpenicillin 435
Box 19.4 Pseudomonas aeruginosa 438
Box 19.5 The isoxazolyl penicillins 444
Box 19.6 Clinical aspects of p-lactamase-resistant
penicillins 444
Box 19.7 Ampicillin prodrugs 446
Box 19.8 Clinical aspects of broad-spectrum penicillins 447
Box 19.9 Synthesis of 3-methylated cephalosporins 451
Box 19.10 Clinical aspects of cephalosporins 454
Box 19.11 Clinical aspects of miscellaneous p-lactam
antibiotics 456
Box 19.12 Clinical aspects of cycloserine, bacitracin,
and vancomycin 454
Box 19.13 Clinical aspects of drugs acting on the
plasma membrane
Box 19.14 Clinical aspects of aminoglycosides
Box 19.15 Clinical aspects of tetracyclines and
chloramphenicol
Box 19.16 Clinical aspects of macrolides,
lincosamides, streptogramins,
oxazolidinones, and pleuromutilins
Box 19.17 Synthesis of ciprofloxacin
Box 19.18 Clinical aspects of quinolones and
fluoroquinolones
Box 19.19 Clinical aspects of rifamycins and
miscellaneous agents
Box 19.20 Qrganoarserticals as antiparasitic drugs
20 Antiviral agents
20.1 Viruses and viral diseases
20.2 Structure of viruses
20.3 Life cycle of viruses
20.4 Vaccination
20.5 Antiviral drugs: general principles
20.6 Antiviral drugs used against DNA viruses
20.6.1 Inhibitors of viral DNA polymerase
20.6.2 Inhibitors of tubulin polymerization
20.6.3 Antisense therapy
20.7 Antiviral drugs acting against RNA viruses:
the human immunodeficiency virus (HIV)
20.7.1 Structure and life cycle of HIV
20.7.2 Antiviral therapy against HIV
20.7.3 Inhibitors of viral reverse transcriptase
20.7.3.1 Nucleoside reverse transcriptase
465
468
472
477
479
480
482
487
490
490
490
491
492
493
494
494
498
498
498
498
500
500
500
20.7.4
inhibitors
20.7.3.2 Non-nucleoside reverse
transcriptase inhibitors
Protease inhibitors
20.7.4.1 The HIV protease enzyme
20.7.4.2 Design of HIV protease inhibitors
20.7.4.3 Saquinavir
20.7.4.4 Ritonavir and lopinavir
20.7.4.5 Indinavir
20.7.4.6 Nelfinavir
20.7.4.7 Palinavir
20.7.4.8 Amprenavir and darunavir
20.7.4.9 Atazanavir
20.7.4.10 Tipranavir
20.7.4.11 Alternative design strategies for
antiviral drugs targeting the
HIV protease enzyme
Inhibitors of other targets
20.8 Antiviral drugs acting against RNA viruses:
flu virus
20.8.1 Structure and life cycle of the influenza virus 519
20.8.2 Ion channel disrupters: adamantanes 521
20.7.5
501
504
504
505
507
508
512
513
514
514
514
515
516
517
519
Detailed contents xxi
20.8.3 Neuraminidase inhibitors 522
20.8.3.1 Structure and mechanism of
neuraminidase 522
20.8.3.2 Transition-state inhibitors:
development of zanamivir
(Relenza) 524
20.8.3.3 Transition-state inhibitors:
6-carboxamides 525
20.8.3.4 Carbocyclic analogues:
development of oseltamivir
(Tamiflu) 526
20.8.3.5 Other ring systems 528
20.8.3.6 Resistance studies 529
20.9 Antiviral drugs acting against RNA viruses:
cold virus 530
20.10 Antiviral drugs acting against RNA viruses:
hepatitis C 531
20.10.1 Inhibitors of HCV NS3-4A protease 532
20.10.1.1 Introduction 532
20.10.1.2 Design ofboceprevir and telaprevir 532
20.10.1.3 Second-generation protease
inhibitors 534
20.10.2 Inhibitors of HCV NS5B RNA-dependent
RNA polymerase 535
20.10.3 Inhibitors of HCV NS5A protein 535
20.10.4 Other targets 538
20.11 Broad-spectrum antiviral agents 539
20.11.1 Agents acting against cytidine
triphosphate synthetase 539
20.11.2 Agents acting against
S-adenosylhomocysteine hydrolase 539
20.11.3 Ribavirin 540
20.11.4 Interferons 540
20.11.5 Antibodies and ribozymes 540
20.12 Bioterrorism and smallpox 541
Box 20.1 Clinical aspects of viral DNA polymerase
inhibitors 497
Box 20.2 Clinical aspects of antiviral drugs used
against HIV 501
Box 20.3 Clinical aspects of reverse transcriptase
inhibitors 503
Box 20.4 Clinical aspects of protease inhibitors 516
Box 20.5 Clinical aspects of antiviral agents used in
the treatment of hepatitis C 538
21 Anticancer agents 543
21.1 Cancer: an introduction 543
21.1.1 Definitions 543
21.1.2 Causes of cancer 543
21.1.3 Genetic faults leading to cancer:
proto-oncogenes and oncogenes 543
21.1.3.1 Activation of proto-oncogenes 543
21.1.3.2 lnactivation of tumour suppression
genes (anti-oncogenes) 544
21.1.3.3 The consequences of genetic
defects 544
21.1.4 Abnormal signalling pathways 544
21.1.5 Insensitivity to growth-inhibitory signals 545
21.1.6 Abnormalities in cell cycle regulation 545
21.1.7 Apoptosis and the p53 protein 547
21.1.8 Telomeres 548
21.1.9 Angiogenesis 549
21.1.10 Tissue invasion and metastasis 550
21.1.11 Treatment of cancer 550
21.1.12 Resistance 552
21.2 Drugs acting directly on nucleic acids 553
21.2.1 Intercalating agents 553
21.2.2 Non-intercalating agents which inhibit the
action of topoisomerase enzymes on DNA 555
21.2.2.1 Podophyllotoxins 555
21.2.2.2 Camptothecins 555
21.2.3 Alkylating and metallating agents 555
21.2.3.1 Nitrogen mustards 556
21.2.3.2 Cisplatin and cisplatin
analogues: metallating agents 558
21.2.3.3 CC 1065 analogues 558
21.2.3.4 Other alkylating agents 558
21.2.4 Chain cutters 559
21.2.5 Antisense therapy 559
21.3 Drugs acting on enzymes: antimetabolites 560
21.3.1 Dihydrofolate reductase inhibitors 560
21.3.2 Inhibitors of thymidylate synthase 561
21.3.3 Inhibitors of ribonucleotide reductase 563
21.3.4 Inhibitors of adenosine deaminase 564
21.3.5 Inhibitors of DNA polymerases 564
21.3.6 Purine antagonists 565
21.4 Hormone-based therapies 567
21.4.1 Glucocorticoids, estrogens, progestins,
and androgens 567
21.4.2 Luteinizing hormone-releasing hormone
receptor agonists and antagonists 568
21.4.3 Anti-estrogens 568
21.4.4 Anti-androgens 568
21.4.5 Aromatase inhibitors 570
21.5 Drugs acting on structural proteins 572
21.5.1 Agents which inhibit tubulin polymerization 572
21.5.2 Agents which inhibit tubulin
depolymerization 573
21.6 Inhibitors of signalling pathways 575
21.6.1 Inhibition of farnesyl transferase and
the Ras protein 575
21.6.2 Protein kinase inhibitors 577
21.6.2.1 Kinase inhibitors of the epidermal
growth factor receptor (EGFR) 579
21.6.2.2 Kinase inhibitors of Abelson
tyrosine kinase, c-KIT, PDGFR,
and SRC 582
21.6.2.3 Inhibitors of cyclin-dependent
kinases (CDKs) 586
21.6.2.4 Kinase inhibitors of the MAPK
signal transduction pathway 587
21.6.2.5 Kinase inhibitors of PI3K-PIP3
pathways 588
xxii Detailed contents
21.6.2.6 Kinase inhibitors of anaplastic
lymphoma kinase (ALK) 589
21.6.2.7 Kinase inhibitors of RET and
KIF5B-RET 590
21.6.2.8 Kinase inhibitors of Janus kinase 590
21.6.2.9 Kinase inhibitors of vascular
endothelial growth factor receptor
(VEGFR) 591
21.6.2.10 Multi-receptor tyrosine kinase
inhibitors 591
21.6.2.11 Kinase inhibition involving
protein-protein binding
interactions 595
21.6.3 Receptor antagonists of the hedgehog
signalling pathway 595
21.7 Miscellaneous enzyme inhibitors 596
21.7.1 Matrix metalloproteinase inhibitors 596
21.7.2 Proteasome inhibitors 597
21.7.3 Histone deacetylase inhibitors 600
21.7.4 Inhibitors of poly ADP ribose polymerase 602
21.7.5 Other enzyme targets 603
21.8 Agents affecting apoptosis 603
21.9 Miscellaneous anticancer agents 604
21.9.1 Synthetic agents 605
21.9.2 Natural products 606
21.9.3 Protein therapy 608
21.9.4 Modulation of transcription
factor-coactivator interactions 608
21.10 Antibodies, antibody conjugates, and gene therapy 609
21.10.1 Monoclonal antibodies 609
21.10.2 Antibody-drug conjugates 611
21.10.3 Antibody-directed enzyme prodrug therapy
(ADEPT) 612
21.10.4 Antibody-directed abzyme prodrug therapy
(ADAPT) 614
21.10.5 Gene-directed enzyme prodrug therapy
(GDEPT) 614
21.10.6 Other forms of gene therapy 615
21.11 Photodynamic therapy
21.12 Viral therapy
Box 21.1 Clinical aspects of intercalating agents
Box 21.2 Clinical aspects of non-intercalating agents
inhibiting the action of topoisomerase enzymes
on DNA
Box 21.3 Clinical aspects of alkylating and metallating
agents
Box 21.4 Clinical aspects of antimetabolites
Box 21.5 Clinical aspects of hormone-based therapies
Box 21.6 Clinical aspects of drugs acting on
structural proteins
Box 21.7 General synthesis of gefitinib and related
analogues
Box 21.8 General synthesis of imatinib and analogues
Box 21.9 Design of sorafenib
Box 21.10 Clinical aspects of kinase inhibitors
615
616
554
556
559
565
571
575
582
586
592
593
Box 21.11 Clinical aspects of antibodies and
antibody-drug conjugates 09
Box 21.12 Gemtuzumab ozogamicin: an antibody-drug
conjugate 613
22 Cholinergics, anticholinergics,
and anticholinesterases 620
22.1 The peripheral nervous system - ¦ 620
22.2 Motor nerves of the peripheral nervous system 620
22.2.1 The somatic motor nervous system 621
22.2.2 The autonomic motor nervous system 621
22.2.3 The enteric system 622
22.2.4 Defects in motor nerve transmission 622
22.3 The cholinergic system 622
22.3.1 The cholinergic signalling system 622
22.3.2 Presynaptic control systems 623
22.3.3 Cotransmitters 623
22.4 Agonists at the cholinergic receptor 623
22.5 Acetylcholine^ structure, SAR, and receptor
binding 624
22.6 The instability of acetylcholine . ; 626
22.7 Design of acetylcholine analogues 627
22.7.1 Steric shields 627
22.7.2 Electronic effects 627
22.7.3 Combining steric and electronic effects 628
22.8 Clinical uses for cholinergic agonists 628
22.8.1 Muscarinic agonists 628
22.8.2 Nicotinic agonists 628
22.9 Antagonists of the muscarinic cholinergic receptor 629
22.9.1 Actions and uses of muscarinic antagonists 629
22.9.2 Muscarinic antagonists 629
22.9.2.1 Atropine and hyoscine 629
22.9.2.2 Structural analogues of atropine
and hyoscine 631
22.9.2.3 Simplified analogues of atropine 631
22.9.2.4 Quinuclidine muscarinic agents 633
22.9.2.5 Other muscarinic antagonists 633
22.10 Antagonists of the nicotinic cholinergic receptor 635
22.10.1 Applications of nicotinic antagonists 63 5
22.10.2 Nicotinic antagonists 635
22.10.2.1 Curare and tubocurarine 635
22.10.2.2 Decamethonium and
suxamethonium 636
22.10.2.3 Steroidal neuromuscular
blocking agents 63 7
22.10.2.4 Atracurium and mivacurium 637
22.10.2.5 Other nicotinic antagonists 638
22.11 Receptor structures 539
22.12 Anticholinesterases and acetylcholinesterase 640
22.12.1 Effect of anticholinesterases 640
22.12.2 Structure of the acetylcholinesterase enzyme 640
22.12.3 The active site of acetylcholinesterase 640
22.12.3.1 Crucial amino acids within
the active site 641
22.12.3.2 Mechanism of hydrolysis 641
Detailed contents xxiii
22.13 Anticholinesterase drugs 642
22.13.1 Carbamates 642
22.13.1.1 Physostigmine 642
22.13.1.2 Analogues of physostigmine 644
22.13.2 Organophosphorus compounds 645
22.13.2.1 Nerve agents 645
22.13.2.2 Medicines 646
22.13.2.3 Insecticides 646
22.14 Pralidoxime: an organophosphate antidote 647
22.15 Anticholinesterases as smart drugs 648
22.15.1 Acetylcholinesterase inhibitors 648
22.15.2 Dual-action agents acting on
the acetylcholinesterase enzyme 649
22.15.3 Multi-targeted agents acting on the
acetylcholinesterase enzyme and the
muscarinic M2 receptor 650
Box 22.1 Clinical applications for muscarinic antagonists 634
Box 22.2 Muscarinic antagonists for the treatment
of COPD 634
Box 22.3 Mosses play it smart 652
23.11.3.3 Selective p,-blockers
(second-generation p-blockers)
669
669
672
23 Drugs acting on the adrenergic
nervous system
23.1 The adrenergic nervous system
23.1.1 Peripheral nervous system
23.1.2 Central nervous system
23.2 Adrenergic receptors
23.2.1 Types of adrenergic receptor
23.2.2 Distribution of receptors
654
654
654
654
654
654
655
23.3 Endogenous agonists for the adrenergic receptors 656
23.4 Biosynthesis of catecholamines 656
23.5 Metabolism of catecholamines 657
23.6 Neurotransmission 657
23.6.1 The neurotransmission process 657
23.6.2 Cotransmitters 657
23.6.3 Presynaptic receptors and control 658
23.7 Drug targets 659
23.8 The adrenergic binding site 659
23.9 Structure-activity relationships 660
23.9.1 Important binding groups on
catecholamines 660
23.9.2 Selectivity for a- versus
p-adrenoceptors 661
23.10 Adrenergic agonists 662
23.10.1 General adrenergic agonists 662
23.10.2 o^-, a2-, P,-, and p3-Agonists 662
23.10.3 P2-Agonists and the treatment of asthma 663
23.11 Adrenergic receptor antagonists 666
23.11.1 General a/p-blockers 666
23.11.2 a-Blockers 666
23.11.3 p-Blockers as cardiovascular drugs 667
23.11.3.1 First-generation P-blockers 667
23.11.3.2 Structure-activity relationships of
aryloxypropanolamines 668
672
672
23.11.3.4 Short-acting P-blockers
23.12 Other drugs affecting adrenergic transmission
23.12.1 Drugs that affect the biosynthesis
of adrenergics
23.12.2 Drugs inhibiting the uptake of
noradrenaline into storage vesicles
23.12.3 Release of noradrenaline from storage vesicles 673
23.12.4 Reuptake inhibitors of noradrenaline into
presynaptic neurons 673
23.12.5 Inhibition of metabolic enzymes 675
Box 23.1 Clinical aspects of adrenergic agents 656
Box 23.2 Synthesis of salbutamol 664
Box 23.3 Synthesis of aryloxypropanolamines 668
Box 23.4 Clinical aspects of p-blockers 670
24 The opioid analgesics 678
24.1 History of opium 678
24.2 The active principle: morphine 678
24.2.1 Isolation of morphine 678
24.2.2 Structure and properties 679
24.3 Structure-activity relationships 679
24.4 The molecular target for morphine: opioid
receptors 682
24.5 Morphine: pharmacodynamics and
pharmacokinetics 682
24.6 Morphine analogues 684
24.6.1 Variation of substituents 684
Drug extension 684
Simplification or drug dissection 686
24.6.3.1 Removing ring E 686
24.6.3.2 Removing ring D 686
24.6.3.3 Removing rings C and D 687
24.6.3.4 Removing rings B, C, and D 688
24.6.3.5 Removing rings B, C, D, and E 689
24.6.4 Rigidification 690
24.7 Agonists and antagonists 693
24.8 Endogenous opioid peptides and opioids 695
24.8.1 Endogenous opioid peptides 695
24.8.2 Analogues of enkephalins and 6-selective
opioids 696
Binding theories for enkephalins 697
Inhibitors of peptidases 699
Endogenous morphine 699
24.9 The future 700
24.9.1 The message-address concept 700
Receptor dimers 700
Selective opioid agonists versus
multi-targeted opioids 701
24.9.4 Peripheral-acting opioids 701
24.10 Case study: design of nalfurafine 701
Box 24.1 Clinical aspects of morphine 679
Box 24.2 Synthesis of/V-alkylated morphine analogues 685
24.6.2
24.6.3
24.8.3
24.8.4
24.8.5
24.9.2
24.9.3
xxiv Detailed contents
Box 24.3 Opioids as antidiarrhoeal agents
690
26 Cardiovascular drugs
735
735
735
Box 24.4 Synthesis of the orvinols
692
26.1 Introduction
Box 24.5 A comparison of opioids and their effects
26.2 The cardiovascular system
on opioid receptors
695
26.3 Antihypertensives affecting the activity of
737
737
Box 24.6 Design of naltrindole
698
the RAAS system
705
, 26.3.1 Introduction
25 Anti-ulcer agents
26.3.2 Renin inhibitors
737
25.1 Peptic ulcers
705
26.3.3 ACE inhibitors
738
25.1.1 Definition !•
705
26.3.4 Angiotensin receptor antagonists
739
25.1.2 Causes
705
26.3.5 Mineralocorticoid receptor antagonists
741
25.1.3 Treatment r
705
26.3.6 Dual-action agents
742
25.1.4 Gastric acid release
705
26.4 Endothelin receptor antagonists as
25.2 H2 antagonists
706
antihypertensive agents
742
25.2.1 Histamine and histamine receptors
707
26.4.1 Endothelins and endothelin receptors
742
25.2.2 Searching for a lead
708
26.4.2 Endothelin antagonists
742
25.2.2.1 Histamine
708
* 26.4.3 Dual-action agents
743
25.2.2.2 Nu-Guanylhistamine
25.2.3 Developing the lead:
708
26.5 Vasodilators
744
a chelation bonding theory
711
26.5.1 Modulators of soluble guanylate cyclase
744
25.2.4 From partial agonist to antagonist:
26.5.2 Phosphodiesterase type 5 inhibitors
746
the development of burimamide
711
26.5.3 Neprilysin inhibitors
747
25.2.5 Development of metiamide
713
26.5.4 Prostacyclin agonists
747
25.2.6 Development of cimetidine Ji
716
26.5.5 Miscellaneous vasodilators
747
25.2.7 Cimetidine
717
26.6 Calcium entry blockers
748
25.2.7.1 Biological activity
717
26.6.1 Introduction
748
25.2.7.2 Structure and activity
718
26.6.2 Dihydropyridines
750
25.2.7.3 Metabolism
718
26.6.3 Phenylalkylamines
751
25.2.8 Further studies of cimetidine
analogues
719
26.6.4 Benzothiazepines
752
25.2.8.1 Conformational isomers
719
26.7 Funny ion channel inhibitors
753
25.2.8.2 Desolvation
720
26.8 Lipid-regulating agents
754
25.2.8.3 Development of the
26.8.1 Statins
754
nitroketeneaminal binding group
720
26.8.2 Fibrates
754
25.2.9 Further H2 antagonists
722
26.8.3 Dual- and pan-PPAR agonists
755
25.2.9.1 Ranitidine
722
26.8.4 Antisense drugs
756
25.2.9.2 Famotidine and nizatidine
723
26.8.5 Inhibitors of transfer proteins
756
25.2.9.3 H2 antagonists with prolonged
26.8.6 Antibodies as lipid-Iowering agents
756
activity
724
26.9 Antithrombotic agents
757
25.2.10 Comparison of H, and H2
antagonists
724
26.9.1 Anticoagulants
26.9.1.1 Introduction
758
758
25.2.11 H2 receptors and H2 antagonists
725
26.9.1.2 Direct thrombin inhibitors
758
25.3 Proton pump inhibitors
725
26.9.1.3 Factor Xa inhibitors
759
25.3.1 Parietal cells and the proton pump
725
26.9.2 Antiplatelet agents
760
25.3.2 Proton pump inhibitors
726
26.9.2.1 Introduction
760
25.3.3 Mechanism of inhibition
727
26.9.2.2 PAR-1 antagonists
760
25.3.4 Metabolism of proton pump inhibitors
728
26.9.2.3 P2Y12 antagonists
761
25.3.5 Design of omeprazole and esomeprazole
728
26.9.2.4 Gpllb/illa antagonists
763
25.3.6 Other proton pump inhibitors
731
26.9.3 Fibrinolytic drugs
763
25,4 Helicobacter pylori and the use of
Box 26.1 Synthesis of dihydropyridines
749
antibacterial agents
25.4.1 Discovery of Helicobacter pylori
732
732
Case study 6: Steroidal anti-inflammatory agents
766
25.4.2 Treatment
732
¦ CS6.1 Introduction to steroids
766
25.5 Traditional and herbal medicines
733
¦ CS6.2 Orally active analogues of Cortisol
767
Box 25.1 Synthesis of cimetidine
718
¦ CS6.3 Topical glucocorticoids as
Box 25.2 Synthesis of omeprazole and esomeprazole
731
anti-inflammatory agents
768
Detailed contents xxv
Case study 7: Current research into antidepressant
¦ CS9.6 The development of rivoraxaban
793
agents
776
¦ CS9.7 The development of edoxaban
794
¦ CS7.1 Introduction
776
Case study 10: Reversible inhibitors of
¦ CS7.2 The monoamine hypothesis
776
HCV NS3-4A protease
795
¦ CS7.3 Current antidepressant agents
776
¦ CS10.1 Introduction
795
¦ CS7.4 Current areas of research
777
¦ CS10.2 Identification of a lead compound
795
¦ CS7.5 Antagonists for the 5-HT7 receptor
777
¦ CS10.3 Modifications of the lead compound
796
Case study 8: The design and development of aliskiren
781
¦ CS10.4 From hexapeptide to tripeptide
797
¦ CS8.1 Introduction
781
¦ CS10.5 From tripeptide to macrocycle
¦ CS8.2 Reaction catalysed by renin
781
(BILN-2061)
798
¦ CS8.3 From lead compound to peptide inhibitors 781
¦ CS10.6 From BILN-2061 to simeprevir
799
¦ CS8.4 Peptidomimetic strategies
783
Appendix 1 Essential amino acids
801
¦ CS8.5 Design of non-peptide inhibitors
783
Appendix 2 The standard genetic code
802
¦ CS8.6 Optimization of the structure
785
Appendix 3 Statistical data for QSAR
803
Case study 9: Factor Xa inhibitors
788
Appendix 4 The action of nerves
807
Appendix 5 Microorganisms
811
¦ CS9.1 Introduction
788
Appendix 6 Trade names and drugs
813
¦ CS9.2 The target
788
Appendix 7 Hydrogen bonding interactions
822
¦ CS9.3 General strategies in the design
Glossary
824
of factor Xa inhibitors
789
General further reading
845
¦ CS9.4 Apixaban: from hit structure to
Index
847
lead compound
789
¦ CS9.5 Apixaban: from lead compound
to final structure 790
|
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| author | Patrick, Graham L. |
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| classification_tum | MED 960 CHE 893 |
| ctrlnum | (OCoLC)987877470 (DE-599)BVBBV044254714 |
| discipline | Chemie / Pharmazie Chemie Medizin |
| edition | Sixth edition |
| format | Book |
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| id | DE-604.BV044254714 |
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| indexdate | 2024-07-10T07:47:53Z |
| institution | BVB |
| isbn | 9780198749691 |
| language | English |
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| physical | xxxi, 877 Seiten Illustrationen, Diagramme |
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| spelling | Patrick, Graham L. Verfasser (DE-588)108943457X aut An introduction to medicinal chemistry Graham L. Patrick Sixth edition Oxford Oxford University Press [2017] © 2017 xxxi, 877 Seiten Illustrationen, Diagramme txt rdacontent n rdamedia nc rdacarrier Pharmazeutische Chemie (DE-588)4132158-3 gnd rswk-swf Physiologische Chemie (DE-588)4076124-1 gnd rswk-swf (DE-588)4151278-9 Einführung gnd-content Pharmazeutische Chemie (DE-588)4132158-3 s DE-604 Physiologische Chemie (DE-588)4076124-1 s 1\p DE-604 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=029659751&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis 1\p cgwrk 20201028 DE-101 https://d-nb.info/provenance/plan#cgwrk |
| spellingShingle | Patrick, Graham L. An introduction to medicinal chemistry Pharmazeutische Chemie (DE-588)4132158-3 gnd Physiologische Chemie (DE-588)4076124-1 gnd |
| subject_GND | (DE-588)4132158-3 (DE-588)4076124-1 (DE-588)4151278-9 |
| title | An introduction to medicinal chemistry |
| title_auth | An introduction to medicinal chemistry |
| title_exact_search | An introduction to medicinal chemistry |
| title_full | An introduction to medicinal chemistry Graham L. Patrick |
| title_fullStr | An introduction to medicinal chemistry Graham L. Patrick |
| title_full_unstemmed | An introduction to medicinal chemistry Graham L. Patrick |
| title_short | An introduction to medicinal chemistry |
| title_sort | an introduction to medicinal chemistry |
| topic | Pharmazeutische Chemie (DE-588)4132158-3 gnd Physiologische Chemie (DE-588)4076124-1 gnd |
| topic_facet | Pharmazeutische Chemie Physiologische Chemie Einführung |
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