An Introduction to

Medicinal ChemistryTHIRD EDITION

Graham L. Patrick

OXPORDUNIVERSITY PRESS

LIST OF BOXES

ACRONYMS AND ABBREVIATIONS

CLASSIFICATION OF DRUGS

1 By pharmacological effect

2 By chemical structure

3 By target system

4 By site of action

NAMING OF DRUGS

PART A Pharmacodynamics and

pharmacokinetics

1 Drugs and the medicinal chemist

2 The why and the wherefore: drug targets

2.1 Why should drugs work?

2.2 Where do drugs work?

2.2.1 Cell structure

2.2.2 Drug targets at the molecular level

2.3 Intermolecular bonding forces

2.3.1 Electrostatic or ionic bonds

2.3.2 Hydrogen bonds

2.3.3 Van der Waals interactions

2.3.4 Dipole—dipole and ion-dipole interactions

2.3.5 Repulsive interactions

2.3.6 The rale of water and

hydrophobic interactions

2.4 Drug targets

2.4.1 Lipids as drug targets

2.4.2 Carbohydrates as drug targets

2.4.3 Proteins and nucleic acids as drug targets

3 Proteins as drug targets

3.1 Primary structure of proteins

3.2 Secondary structure of proteins

3.2.1 α-helix

3.2.2 β-pleated sheet

3.2.3 β-turn

3.3 Tertiary structure of proteins

3.3.1 Covalent bonds

3.3.2 Ionic bonds

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3.3.3 Hydrogen bonds

3.3.4 Van der Waals and hydrophobic interactions

3.3.5 Relative importance of bonding interactions

3.3.6 Role of the planar peptide bond

3.4 Quaternary structure of proteins

3.5 Post-translational modifications

3.6 Proteomics

3.7 Drug action at proteins

3.7.1 Carrier proteins

3.7.2 Structural proteins

3.8 Peptides or proteins as drugs

3.9 Monoclonal antibodies in medicinal chemistry

4 Proteins as drug targets: enzymes

4.1 Enzymes as catalysts

4.2 How do enzymes lower activation energies?

4.3 The active site of an enzyme

4.4 Substrate binding at an active site

4.5 The catalytic role of enzymes

4.5.1 Binding interactions

4.5.2 Acid-base catalysis

4.5.3 Nucleophilic groups

4.5.4 Cofactors

4.5.5 Naming and classification of enzymes

4.6 Regulation of enzymes

4.7 Isozymes

4.8 Enzyme inhibitors

4.8.1 Competitive (reversible) inhibitors

4.8.2 Non-competitive (irreversible) inhibitors

4.8.3 Non-competitive, reversible (allosteric)

inhibitors

4.8.4 Transition-state analogues—renininhibitors

4.8.5 Suicide substrates

4.8.6 Isozyme selectivity of inhibitors

4.8.7 Medicinal uses of enzyme inhibitors

4.8.7.1 Enzyme inhibitors used against

microorganisms

4.8.7.2 Enzyme inhibitors used against viruses

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4.8.7.3 Enzyme inhibitors used against

the body's own enzymes

4.9 Enzyme kinetics

4.9.1 The Michaelis—Menten equation

4.9.2 Lineweaver-Burk plots

4.9.3 Comparison of inhibitors

5 Proteins as drug targets: receptors

5.1 The receptor role

5.2 Neurotransmitters and hormones

5.3 Receptors

5.4 How is the message received?

5.4.1 Ion channels and their control

5.4.2 Membrane-bound enzyme activation

5.5 How does a receptor change shape?

5.6 The design of agonists

5.6.1 Binding groups

5.6.2 Position of binding groups

5.6.3 Size and shape

5.6.4 Pharmacodynamics and pharmacokinetics

5.7 Design of antagonists

5.7.1 Antagonists acting at the binding site

5.7.2 Antagonists acting outwith the

binding site

5.8 Partial agonists

5.9 Inverse agonists

5.10 Desensitization and sensitization

5.11 Tolerance and dependence

5.12 Cytoplasmic receptors

5.13 Receptor types and subtypes

5.14 Affinity, efficacy, and potency

6 Proteins as drug targets: receptor structure

and signal transduction

6.1 Receptor families

6.2 Receptors that control ion channels

(ligand-gated ion channel receptors)

6.2.1 Structure and function of 4-TM ion

channel receptors

6.2.2 3-TM ion channel receptors

6.2.3 2-TM ion channel receptors

6.3 Structure of G-protein-coupled receptors

6.3.1 Structure of G-protein-coupled receptors

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6.3.2 Neurotransmitters and hormones tor

G-protein-coupled receptors

6.3.3 Ligand binding

6.3.4 The rhodopsin-like family of

G-protein-coupled receptors

6.4 Signal transduction pathways for

G-protein-coupled receptors

6.4.1 Interaction of the 7-TM receptor-ligand

complex with G-proteins

6.4.2 Signal transduction pathways involving

the α-subunit

6.5 Signal transduction involving G-protein-coupled

receptors and cyclic AMP

6.5.1 Activation of adenylate cyclase by the

ots-subunit

6.5.2 Activation of protein kinase A

6.5.3 The G,-protein

6.5.4 General points about the signalling cascade

involving cAMP

6.5.5 The role of the Py-dimer

6.5.6 Phosphorylation

6.6 Signal transduction involving

G-protein-coupled receptors and

phospholipase C

6.6.1 Activation by phospholipase C

6.6.2 Action of the secondary messenger

diacylglycerol

6.6.3 Action of the secondary messenger

inositol triphosphate

6.6.4 Resynthesis of phosphatidylinositol

diphosphate

6.7 Kinase-linked (1-TM) receptors

6.7.1 Structure of kinase-linked receptors

6.7.2 Signalling mechanism for the tyrosine kinase

receptor family

6.7.3 Interaction of protein kinase receptors with

signalling proteins

6.7.4 Small G-proteins

6.7.5 Activation of guanylate cyclase by

1-TM receptors

6.8 Intracellular receptors

7 Nucleic acids as drug targets

7.1 Structure of DNA

7.1.1 The primary structure of DNA

7.1.2 The secondary structure of DNA

7.1.3 The tertiary structure of DNA

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7.2 Ribonucleic acid and protein synthesis

7.2.1 Structure of RNA

7.2.2 Transcription and translation

7.2.3 Small nuclear RNA

7.3 Drugs and nucleic acids

7.4 Antisense therapy

7.5 Genetic illnesses

7.6 Molecular biology and geneticengineering

8 Pharmacokinetics and related topics

8.1 Pharmacodynamics and pharmacokinetics

8.2 Drug absorption

8.3 Drug distribution

8.3.1 Distribution round the blood supply

8.3.2 Distribution to tissues

8.3.3 Distribution to cells

8.3.4 Other distribution factors

8.3.5 Blood-brain barrier

8.3.6 Placental barrier

8.3.7 Drug-drug interactions

8.4 Drug metabolism

8.4.1 Phase I and phase II metabolism

8.4.2 Phase I transformations catalysed bycytochrome P450 enzymes

8.4.3 Phase I transformations catalysed byflavin-containing monooxygenases

8.4.4 Phase I transformations catalysed byother enzymes

8.4.5 Phase II transformations

8.4.6 Metabolic stability

8.4.7 The first pass effect

8.5 Drug excretion

8.6 Drug administration

8.6.1 Oral administration

8.6.2 Absorption through mucous membranes

8.6.3 Rectal administration

8.6.4 Topical administration

8.6.5 Inhalation

8.6.6 Injection

8.6.7 Implants

8.7 Drug dosing

8.7.1 Drug half-life

8.7.2 Steady state concentration. 1

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PART E

9 Drug

9.1

9.2

9.3

9.4

DETAILED CONTENTS

8.7.3 Drug tolerance

8.7.4 Bioavailability

Formulation

Drug delivery

Drug discovery, design, anddevelopment

discovery: finding a lead

Choosing a disease

Choosing a drug target

9.2.1 Drug targets

9.2.2 Discovering drug targets

9.2.3 Target specificity and selectivitybetween species

9.2.4 Target specificity and selectivity withinthe body

9.2.5 Targeting drugs to specific organs

and tissues

9.2.6 Pitfalls

Identifying a bioassay

9.3.1 Choice of bioassay

9.3.2 In vitro tests

9.3.3 In vivo tests

9.3.4 Test validity

9.3.5 High-throughput screening

9.3.6 Screening by NMR

9.3.7 Affinity screening

9.3.8 Surface plasmon resonance

9.3.9 Scintillation proximity assay

Finding a lead compound

9.4.1 Screening of natural products

9.4.1.1 The plant kingdom

9.4.1.2 The microbial world

9.4.1.3 The marine world

9.4.1.4 Animal sources

9.4.1.5 Venoms and toxins9.4.2 Medical folklore

9.4.3 Screening synthetic compound libraries'

9.4.4 Existing drugs

9.4.4.1 'Me too' drugs

9.4.4.2 Enhancing a side effect

9.4.5 Starting from the natural ligandor modulator

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9.4.5.1 Natural ligands for receptors 177

9.4.5.2 Natural substrates for enzymes 177

9.4.5.3 Enzyme products as lead compounds 178

9.4.5.4 Natural modulators as lead compounds 178

9.4.6 Combinatorial synthesis 178

9.4.7 Computer-aided design 178

9.4.8 Serendipity and the prepared mind 178

9.4.9 Computerized searching of structural databases 180

9.4.10 Designing lead compounds by NMR

9.5 Isolation and purification

9.6 Structure determination

9.7 Herbal medicine

10 Drug design: optimizing target interactions

10.1 Structure-activity relationships

10.1.1 Binding role of alcohols and phenols

10.1.2 Binding role of aromatic rings

10.1.3 Binding role of alkenes

10.1.4 Binding role of ketones and aldehydes

10.1.5 Binding role of amines

10.1.6 Binding role of amides

10.1.7 Binding role of quaternary ammonium salts

10.1.8 Binding role of carboxylic acids

10.1.9 Binding role of esters

10.1.10 Binding role of alkyl and aryl halides

10.1.11 Binding role of thiols

10.1.12 Binding role of other functional groups

10.1.13 Binding role of alkyl groups and

the carbon skeleton

10.1.14 Binding role of heterocydes

10.1.15 Isosteres

10.1.16 Testing procedures

10.2 Identification of a pharmacophore

10.3 Drug optimization: strategies in drug

design

10.3.1 Variation of substituents

10.3.1.1 Alkyl substituents

10.3.1.2 Aromatic substitutions

10.3.2 Extension of the structure

10.3.3 Chain extension/contraction

10.3.4 Ring expansion/contraction

10.3.5 Ring variations

10.3.6 Ring fusions

10.3.7 Isosteres and bioisosteres

10.3.8 Simplification of the structure

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Drug

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10.3.9 Rigidification of the structure

10.3.10 Conformational blockers

10.3.11 Structure-based drug design and

molecular modelling

10.3.11.1 The tools: X-ray crystallography

and molecular modelling

10.3.11.2 Case study: the design of

ACE inhibitors

10.3.12 Drug design by NMR

10.3.13 The elements of luck and inspiration

A case study: oxamniquine

design: optimizing access to the target

Improving absorption

11.1.1 Variation of alkyl or acyl substituents

to vary polarity

11.1.2 Varying polar functional groups to

vary polarity

11.1.3 Variation of A/-alkyl substituents to

vary pKa

11.1.4 Variation of aromatic substituents to

vary pKa

11.1.5 Bioisosteres for polar groups

Making drugs more resistant to

chemical and enzymatic degradation

11.2.1 Steric shields

11.2.2 Electronic effects of bioisosteres

11.2.3 Stereoelectronic modifications

11.2.4 Metabolic blockers

11.2.5 Removal of susceptible metabolic groups

11.2.6 Group shifts

11.2.7 Ring variation

Making drugs less resistant to drug metabolism

11.3.1 Introducing metabolically susceptible groups

11.3.2 Self-destruct drugs

Targeting drugs

11.4.1 Targeting tumour cells—'search and

destroy' drugs

11.4.2 Targeting gastrointestinal tract infections

11.4.3 Targeting peripheral regions rather than

the central nervous system

Reducing toxicity

Prodrugs

11.6.1 Prodrugs to improve membrane permeability

11.6.1.1 Esters as prodrugs

11.6.1.2 W-Methylation

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11.7

11.8

12 Drug

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,1

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12.3

11.6.1.3 Trojan horse approach for

carrier proteins

11.6.2 Prodrugs to prolong drug activity

11.6.3 Prodrugs masking drug toxicity

and side effects

11.6.4 Prodrugs to lower water solubility

11.6.5 Prodrugs to improve water solubility

11.6.6 Prodrugs used in the targeting of drugs

11.6.7 Prodrugs to increase chemical stability

11.6.8 Prodrugs activated by external influence

(sleeping agents)

Drug alliances

11.7.1 'Sentry' drugs

11.7.2 Localizing a drug's area of activity

11.7.3 Increasing absorption

Endogenous compounds as drugs

11.8.1 Neurotransmitters

11.8.2 Natural hormones as drugs

11.8.3 Peptides and proteins as drugs

11.8.4 Peptidomimetics

11.8.5 Oligonucleotides as drugs—antisense drugs

development

Preclinical and clinical trials

12.1.1 Toxicity testing

12.1.2 Drug metabolism studies

12.1.3 Pharmacology, formulation, and

stability tests

12.1.4 Clinical trials

12.1.4.1 Phase 1 studies

12.1.4.2 Phase II studies

12.1.4.3 Phase III studies

12.1.4.4 Phase IV studies

12.1.4.5 Ethical issues

Patenting and regulatory affairs

12.2.1 Patents

12.2.2 Regulatory affairs

12.2.2.1 The regulatory process

12.2.2.2 Fast tracking and orphan drugs

12.2.2.3 Good laboratory, manufacturing,

and clinical practice

Chemical and process development

12.3.1 Chemical development

12.3.2 Process development

12.3.3 Choice of drug candidate

12.3.4 Natural products

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PART C Tools of the trade

13 Quantitative structure-activityrelationships (QSAR)

13.1 Graphs and equations

13.2 Physicochemical properties

13.2.1 Hydrophobicity

13.2.2 Electronic effects

13.2.3 Steric factors

13.2.3.1 Taft's steric factor (fs)

13.2.3.2 Molar refractivity

13.2.3.3 Verloop steric parameter

13.2.4 Other physicochemical parameters

13.3 Hansch equation

13.4 Craig plot

13.5 Topliss scheme

13.6 Bioisosteres

13.7 Free-Wilson approach

13.8 Planning a QSAR study

13.9 Case study

13.10 3D QSAR

13.10.1 Defining steric and electrostatic fields

13.10.2 Relating shape and electronic

distribution to biological activity

13.10.3 Hydrophobic potential

13.10.4 Advantages of 3D QSAR over

traditional QSAR

13.10.5 Potential problems of 3D QSAR

13.10.6 Case study: inhibitors of

tubulin polymerization

14 Combinatorial synthesis

14.1 Combinatorial synthesis in medicinal

chemistry

14.2 Solid phase techniques

14.2.1 The solid support

14.2.2 The anchor/linker

14.2.3 Protecting groups and synthetic

strategy

14.2.3.1 Boc/benzyl protection strategy

14.2.3.2 Fmoc/f-Bu strategy

14.3 Methods of parallel synthesis

14.3.1 Houghton's teabag procedure

14.3.2 Automated parallel synthesis

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14.4 Methods in mixed combinatorial synthesis

14.4.1 General principles

14.4.2 The mix and split method

14.4.3 Mix and split in the production of

positional scanning libraries

14.5 Isolating the active component in

a mixture: deconvolution

14.5.1 Micromanipulation

14.5.2 Recursive deconvolution

14.5.3 Sequential release

14.6 Structure determination of the

active compound(s)

14.6.1 Tagging

14.6.2 Photolithography

14.7 Limitations of combinatorial synthesis

14.8 Examples of combinatorial syntheses

14.9 Dynamic combinatorial chemistry

14.10 Planning and designing a

combinatorial synthesis

14.10.1 'Spider like' scaffolds

14.10.2 Designing 'drug-like' molecules

14.10.3 Scaffolds

14.10.4 Substituent variation

14.10.5 Designing compound libraries for

lead optimization

14.10.6 Computer-designed libraries

14.11 Testing for activity

14.11.1 High-throughput screening

14.11.2 Screening 'on bead' or 'off bead'

15 Computers in medicinal chemistry

15.1 Molecular and quantum mechanics

15.1.1 Molecular mechanics

15.1.2 Quantum mechanics

15.1.3 Choice of method

15.2 Drawing chemical structures

15.3 3D structures

15.4 Energy minimization

15.5 Viewing 3D molecules

15.6 Molecular dimensions

15.7 Molecular properties

15.7.1 Partial charges

15.7.2 Molecular electrostatic ootentials

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15.7.3 Molecular orbitals

15.7.4 Spectroscopic transitions

Conformational analysis

15.8.1 Local and global energy minima

15.8.2 Molecular dynamics

15.8.3 Stepwise bond rotation

15.8.4 Monte Carlo methods in

conformational searching

Structure comparisons and overlays

Identifying the active conformation

15.10.1 X-ray crystallography

15.10.2 Comparison of rigid and non-rigid ligands

3D pharmacophore identification

15.11.1 X-ray crystallography

15.11.2 Structural comparison of active compounds

15.11.3 Automatic identification of

pharmacophores

Docking procedures

15.12.1 Manual docking

15.12.2 Automatic docking

Automated screening of databases

for lead compounds

Protein mapping

15.14.1 Constructing a model protein

15.14.2 Constructing a binding site

De novo design

15.15.1 Thymidylate synthase inhibitors

15.15.2 Automated de novo design

Planning combinatorial syntheses

Database handling

Case study

15.18.1 The target

15.18.2 Testing procedures

15.18.3 Lead compound to SB 200646

15.18.4 SB 200646 to SB 206553

15.18.5 Analogues of SB 206553

15.18.6 Molecular modelling studies on

SB 206553 and analogues

15.18.7 SB 206553 to SB 221284

15.18.8 Modelling studies on SB 221284

15.18.9 3D QSAR studies on analogues of

SB 221284

15.18.10 SB 221284 to SB 228357

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PART D Selected topics in medicinal chemistry

16 Antibacterial agents

16.1 The history of antibacterial agents

16.2 The bacterial cell

16.3 Mechanisms of antibacterial action

16.4 Antibacterial agents which act against

cell metabolism (antimetabolites)

16.4.1 Sulfonamides

16.4.1.1 The history of sulfonamides

16.4.1.2 Structure-activity relationships

16.4.1.3 Sulfanilamide analogues

16.4.1.4 Applications of sulfonamides

16.4.1.5 Mechanism of action

16.4.2 Examples of other antimetabolites

16.4.2.1 Trimethoprim

16.4.2.2 Sulfones

16.5 Antibacterial agents which inhibit

cell wall synthesis

16.5.1 Penicillins

16.5.1.1 History of penicillins

16.5.1.2 Structure of benzylpenicillin and

phenoxymethylpenicillin

16.5.1.3 Properties of benzylpenicillin

16,5.1.4 Mechanism of action of penicillin

16.5.1.5 Resistance to penicillin•

16.5.1.6 Methods of synthesizing

penicillin analogues

16.5.1.7 Structure-activity relationships

of penicillins

16.5.1.8 Penicillin analogues -

16.5.2 Cephalosporins

16.5.2.1 Cephalosporin C

16.5.2.2 Synthesis of cephalosporin analogues

at the 7-position

16.5.2.3 First-generation cephalosporins

16.5.2.4 Second-generation cephalosporins

16.5.2.5 Third-generation cephalosporins

16.5.2.6 Fourth-generation cephalosporins

16.5.2.7 Resistance to cephalosporins

16.5.3 Other β-lactam antibiotics

16.5.4 p-Lactamase inhibitors

16.5.4.1 Clavutanic acid

16.5.4.2 Penicillanic acid sulfone derivatives

16.5.4.3 Olivanic acids

16.5.5 Other drugs which act on bacterial

cell wall biosynthesis

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DETAILED CONTENTS

16.5.5.1 D-cycloserine and bacitracin

16.5.5.2 The glycopeptides—vancomycin

and vancomycin analogues

16.6 Antibacterial agents which act on

the plasma membrane structure

16.6.1 Valinomycin and gramicidin A

16.6.2 Polymyxin B

16.6.3 Killer nanotubes

16.6.4 Cyclic lipopeptides

16.7 Antibacterial agents which impair protein

synthesis—translation

16.7.1 Aminoglycosides . •

16.7.2 Tetracyclines

16.7.3 Chloramphenicol

16.7.4 Macrolides

16.7.5 Lincosamides

16.7.6 Streptogramins

16.7.7 Oxazolidinones

16.8 Agents which act on nucleic acid

transcription and replication

16.8.1 Quinolones and fluoroquinolones

16.8.2 Aminoacridines

16.8.3 Rifamycins

16.8.4 Nitroimidazoles and nitrofurantoin

16.9 Miscellaneous agents

16.10 Drug resistance

16.10.1 Drug resistance by mutation

16.10.2 Drug resistance by genetic transfer

16.10.3 Other factors affecting drug resistance

16.10.4 The way ahead

17 Antiviral agents

17.1 Viruses and viral diseases

17.2 Structure of viruses

17.3 Life cycle of viruses

17.4 Vaccination

17.5 Antiviral drugs: general principles

17.6 Antiviral drugs used against DNA viruses

17.6.1 Inhibitors of viral DNA polymerase

17.6.2 Inhibitors of tubulin polymerization

17.6.3 Antisense therapy

17.7 Antiviral drugs acting against RNA viruses: HIV

17.7.1 Structure and life cycle of HIV

17.7.2 Antiviral therapy against HIV

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17.8

17.7.3 Inhibitors of viral reverse transcriptase 452

17.7.3.1 Nucleoside reverse transcriptase

inhibitors 452

17.7.3.2 Non-nucleoside reverse transcriptase

inhibitors 453

17.7.4 Protease inhibitors 455

17.7.4.1 The HIV protease enzyme 456

17.7.4.2 Design of HIV protease inhibitors 457

17.7.4.3 Saquinavir 459

17.7.4.4 Ritonavir and lopinavir 462

17.7.4.5 Indinavir 466

17.7.4.6 Nelfinavir 467

17.7.4.7 Palinavir 468

17.7.4.8 Amprenavir 468

17.7.4.9 Atazanavir 469

17.7.5 Inhibitors of other targets 469

Antiviral drugs acting against

RNA viruses: flu virus 471

17.8.1 Structure and life cycle of the

influenza virus 471

17.8.2 Ion channel disrupters: adamantanes 473

17.8.3 Neuraminidase inhibitors 473

17.8.3.1 Structure and mechanism

of neuraminidase 473

17.8.3.2 Transition-state inhibitors:

development of zanamivir (Relenza) 475

17.8.3.3 Transition-state inhibitors:

6-carboxamides 478

17.8.3.4 Carbocydic analogues: development

of oseltamivir (Tamiflu)

17.8.3.5 Other ring systems

17.8.3.6 Resistance studies

17.9 Antiviral drugs acting againstRNA viruses: cold virus

17.10 Broad-spectrum antiviral agents

17.10.1 Agents acting against cytidine

triphosphate synthetase

17.10.2 Agents acting against

5-adenosylhomocysteine hydrolase

17.10.3 Ribavirin (or virazole)

17.10.4 Interferons

17.10.5 Antibodies and ribozymes

17.11 Bioterrorism and smallpox

18 Anticancer agents

18.1 Cancer: an introduction

18.1.1 Definitions

18.1.2 Causes of cancer

479481

482

483

485

485

485

485

486

486

486

489

489

489

489

18.1.3 Genetic faults leading to cancer:

proto-oncogenes and oncogenes

18.1.3.1 Activation of proto-oncogenes

18.1.3.2 Inactivation of tumour suppression

genes (anti-oncogenes)

18.1.4 Abnormal signalling pathways

18.1.5 Insensitivity to growth-inhibitory signals

18.1.6 Abnormalities in cell cycle regulation

18.1.7 Apoptosis and the p53 protein

18.1.8 Telomeres

18.1.9 Angiogenesis

18.1.10 Tissue invasion and metastasis

18.1.11 Treatment of cancer

18.1.12 Resistance

18.2 Drugs acting directly on nucleic acids

18.2.1 Intercalating agents

18.2.2 Non-intercalating agents which inhibit

the action of topoisomerase enzymes

on DNA

18.2.2.1 Podophyllotoxins

18.2.2.2 Camptothecins

18.2.3 Alkylating agents

18.2.3.1 Nitrogen mustards

18.2.3.2 Nitrosoureas

18.2.3.3 Busulfan

18.2.3.4 Cisplatin and cisplatin analogues

18.2.3.5 Dacarbazine and procarbazine

18.2.3.6 Mitomycin C

18.2.3.7 CC 1065 analogues

18.2.4 Chain cutters

18.2.5 Antisense therapy

18.3 Drugs acting on enzymes: antimetabolites

18.3.1 Dihydrofolate reductase inhibitors

18.3.2 Inhibitors of thymidylate synthase

18.3.3 Inhibitors of ribonucleotide reductase

18.3.4 Inhibitors of adenosine deaminase

18.3.5 Inhibitors of DNA polymerases

18.3.6 Purine antagonists

18.4 Hormone-based therapies

18.4.1 Glucocorticoids

18.4.2 Oestrogens

18.4.3 Progestins

18.4.4 Androgens

18.4.5 LHRH agonists

18.4.6 Antioestrogens

18.4.7 Antiandrogens

490

490

490

490

491

491

493

494

495

496

497

499

500

500

504

504

504

505

506

508

509

509

510

511

511

511

511

514

514

515

516

517

518

518

519

519

520

520

520

520

521

521

•

' . - • •

f

pi•>HftS

•>'{S

• : • «

m

18.4.8 Aromatase inhibitors

18.4.9 Adrenocortical suppressors

18.5 Drugs acting on structural proteins

18.5.1 Agents which inhibit tubulin polymerization

18.5.2 Agents which inhibit tubulin

depolymerization

18.6 Inhibitors of signalling pathways

18.6.1 Inhibition of farnesyl transferase and

the Ras protein

18.6.2 Protein kinase inhibitors

18.6.2.1 Kinase inhibitors of the epidermal

growth factor receptor

18.6.2.2 Inhibitors of the Abelson

tyrosine kinase

18.6.2.3 Inhibitors of cyclin-dependent

kinases

18.6.2.4 Kinase inhibitors of FGF-R and

VEGF-R

18.6.2.5 Other kinase targets

18.7 Miscellaneous enzyme inhibitors

18.7.1 Matrix metalloproteinase inhibitors

18.7.2 Cyclooxygenase-2 inhibitors

18.7.3 Proteasome inhibitors

18.7.4 Histone deacetylase inhibitors

18.7.5 Other enzyme targets

18.8 Miscellaneous anticancer agents

18.8.1 Synthetic agents

18.8.2 Natural products

18.8.3 Protein therapy

18.9 Antibodies, antibody conjugates, and

gene therapy

18.9.1 Monoclonal antibodies

18.9.2 Antibody-drug conjugates

18.9.3 Antibody-directed enzyme

prodrug therapy (ADEPT)

18.9.4 Antibody-directed abzyme

prodrug therapy (ADAPT)

18.9.5 Gene-directed enzyme

prodrug therapy (GDEPT)

18.9.6 Other forms of gene therapy

18.10 Photodynamic therapy

19 Cholinergics, anticholinergics,

and anticholinesterases

19.1 The peripheral nervous system

19.2 Motor nerves of the peripheral nervous system

522

522

523

523

525

528

528

531

533

535

538

539

540

540

540

542

543

543

544

544

544

545

546

547

547

548

550

552

552

553

553

558

558

559

19.3

19.4

19.5

19.6

19.7

19.8

19.9

19.10

19.11

19.12

19.13

19.14

19.15

19.16

DETAILED CONTENTS

19.2.1 The somatic motor nervous system

19.2.2 The autonomic motor nervous system

19.2.3 The enteric system

The neurotransmitters

Actions of the peripheral nervous system

The cholinergic system

19.5.1 The cholinergic signalling system

19.5.2 Presynaptic control systems

19.5.3 Co-transmitters

Agonists at the cholinergic receptor

Acetylcholine: structure, SAR, and

receptor binding

The instability of acetylcholine

Design of acetylcholine analogues

19.9.1 Steric shields

19.9.2 Electronic effects

19.9.3 Combining steric and electronic effects

Clinical uses for cholinergic agonists

19.10.1 Muscarinic agonists

19.10.2 Nicotinic agonists

Antagonists of the muscarinic

cholinergic receptor

19.11.1 Actions and uses of muscarinic

antagonists

19.11.2 Muscarinic antagonists

19.11.2.1 Atropine and hyoscine

19.11.2.2 Structural analogues based

on atropine

Antagonists of the nicotinic cholinergic

receptor

19.12.1 Applications of nicotinic antagonists

19.12.2 Nicotinic antagonists

19.12.2.1 Curare and tubocurarine

19.12.2.2 Decamethonium and

suxamethonium

19.12.2.3 Pancuronium and vecuronium

19.12.2.4 Atracurium and mivacurium

Other cholinergic antagonists

Structure of the nicotinic receptor

Structure of the muscarinic receptor

Anticholinesterases and acetylcholinesterase

19.16.1 Effect of anticholinesterases

19.16.2 Structure of the acetylcholinesterase enzyme

xix I

559 I559 1560 1

560 I

561 1

562 1562 I563 I563 I

563 1

565 11567 1

568 1568 1

568 J569 I

569 1569 1570 I

570 I

570 I

571

571 J

572 I

575 1

575 1575 1575 I

576577 1577

579

579

580

581

581

581

XX DETAILED CONTENTS

19.16.3 The active site of acetylcholinesterase

19.16.3.1 Binding interactions at the

active site

19.16.3.2 Mechanism of hydrolysis

19.17 Anticholinesterase drugs

19.17.1 Carbamates

19.17.1.1 Physostigmine

19.17.1.2 Analogues of physostigmine

19.17.2 Organophosphorus compounds

19.17.2.1 Nerve gases

19.17.2.2 Medicines

19.17.2.3 Insecticides

19.18 Pralidoxime: an organophosphate

antidote

19.19 Anticholinesterases as 'smart drugs'

20 The adrenergic nervous system

20.1 The adrenergic system

20.1.1 Peripheral nervous system

20.1.2 The central nervous system

20.2 Adrenergic receptors

20.2.1 Types of adrenergic receptor

20.2.2 Distribution of receptors

20.2.3 Clinical effects

20.3 Endogenous agonists for the

adrenergic receptors

20.4 Biosynthesis of catecholamines

20.5 Metabolism of catecholamines

20.6 Neurotransmission

20.6.1 The neurotransmission process

20.6.2 Co-transmitters

20.6.3 Presynaptic receptors and control

20.7 Drug targets

20.8 The adrenergic binding site

20.9 Structure-activity relationships

20.9.1 Important binding groups on

catecholamines

20.9.2 Selectivity for a- versus

β-adrenoceptors

20.10 Adrenergic agonists

20.10.1 General adrenergic agonists

20.10.2 oti, a 2 , P i , and p3-agonists

20.10.3 P2-Agonists and the treatment

of asthma

581 20.11 Adrenergic receptor antagonists

20.11.1 General ^β-blockers

605

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582

583

583

583

585

586

587

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587

588

589

593

593

593

593

594

594

594

595

r fir

595

595

595

596

596

597

597

598J 17 (J

599

599

599

600

601

601

601

602

20.12

21 The

21.1

21.2

21.3

21.4

20.11.2 tx-Blockers

20.11.3 p-Blockers as cardiovascular drugs

20.11.3.1 First-generation β-blockers

20.11.3.2 Structure-activity relationships of

aryloxypropanolamines

20.11.3.3 Clinical effects of first-generation

β-blockers

20.11.3.4 Selective β^blockers

(second-generation β-blockers)

20.11.3.5 Third-generation β-blockers

20.11.3.6 Other clinical uses for β-blockers

Other drugs affecting adrenergic

transmission

20.12.1 Drugs that affect the biosynthesis

of adrenergics

20.12.2 Uptake of noradrenaline into

storage vesicles

20.12.3 Release of noradrenaline from

storage vesicles

20.12.4 Uptake of noradrenaline into nerve

cells by carrier proteins

20.12.5 Metabolism

opium analgesics

History of opium

Morphine

21.2.1 Isolation of morphine

21.2.2 Structure and properties

21.2.3 Structure-activity relationships

21.2.3.1 Functional groups of

morphine analogues

21.2.3.2 Stereochemistry

Morphine analogues

21.3.1 Variation of substituents

21.3.2 Drug extension

21.3.3 Simplification or drug dissection

21.3.3.1 Removing ring E

21.3.3.2 Removing ring D

21.3.3.3 Removing rings C and D

21.3.3.4 Removing rings B, C, and D

21.3.3.5 Removing rings B, C, D, and E

21.3.4 Rigidification

Receptor theory of analgesics

21.4.1 Beckett-Casy hypothesis

21.4.2 Multiple analgesic receptors

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606

606

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608

609

609

610

611

611

611

611

612

613

616

616

618

618

618

619

619

621

622

622

623

626

626

626

627

627

629

629

632

632

633

21.4.2.1 The μ-receptor

21.4.2.2 The K-receptor

21.4.2.3 The S-receptor

21.5 Agonists and antagonists

21.6 Endogenous opioid peptides

21.6.1 Enkephalins, endorphins, dynorphins,

and endomorphins

21.6.2 Analogues of enkephalins

21.6.3 Inhibitors of peptidases

21.7 Receptor mechanisms

21.7.1 The μ-receptor

21.7.2 The K-receptor

21.7.3 The 5-receptor

21.7.4 The α-receptor

21.8 The future

22 Antiulcer agents

22.1 Peptic ulcers

22.1.1 Definition

22.1.2 Causes

22.1.3 Treatment

22.1.4 Gastric acid release

22.2 H2 antagonists

22.2.1 Histamine and histamine receptors

22.2.2 Searching for a lead

22.2.2.1 Histamine

22.2.2.2 AT-guanylhistamine

22.2.3 Developing the lead: a chelation

bonding theory

22.2.4 From partial agonist to antagonist:

the development of burimamide

22.2.5 Development of metiamide

22.2.6 Development of cimetidine

22.2.7 Cimetidine

22.2.7.1 Biological activity

22.2.7.2 Structure and activity

22.2.7.3 Metabolism

633

633

634

634

636

636

637

637

637

638

639

639

639

639

642

642

642

642

642

642

644

644

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645

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648

650

651

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655

655

656

656

DETAILED CONTENTS

22.2.8 Further studies of cimetidine analogues

22.2.8.1 Conformational isomers

22.2.8.2 Desolvation

22.2.8.3 Development of the

nitroketeneaminal binding group

22.2.9 Further H2 antagonists

22.2.9.1 Ranitidine

22.2.9.2 Famotidine and nizatidine

22.2.9.3 H2 antagonists with prolonged

activity

22.2.10 Comparison of H, and H2 antagonists

22.2.11 H2 receptors and H2 antagonists

22.3 Proton pump inhibitors

22.3.1 Parietal cells and the proton pump

22.3.2 Proton pump inhibitors

22.3.3 Mechanism of inhibition

22.3.4 Metabolism of proton pump inhibitors

22.3.5 Design of omeprazole and esomeprazole

22.3.6 Other proton pump inhibitors

22.4 H. pylori and the use of antibacterial agents

22.4.1 Treatment

22.5 Traditional and herbal medicines

APPENDIX 1 Essential amino acids

APPENDIX 2 The standard genetic code

APPENDIX 3 Statistical data for QSAR

APPENDIX 4 The action of nerves

APPENDIX 5 Microorganisms

Bacterial nomenclature

Some clinically important bacteria

The Gram stain

Classifications

Definitions of different microorganisms

APPENDIX 6 Drugs and their trade names

GLOSSARY

GENERAL FURTHER READING

INDEX

xxi I

656 1656 1658 1

659 1

662 1

662 1

662 1

663 1

663 1

664 1

664 1

664 1

665 I

666 I

667 I

667 1

670 1

671

672

672 i

675

676

677

680

685

685

685

685

685

686

687

695

711

_