Medicinal Chemistry E-Book

Gareth Thomas

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 977

Veröffentlichungsjahr: 2011

Beschreibung

Medicinal Chemistry: An Introduction, Second Edition provides a comprehensive, balanced introduction to this evolving and multidisciplinary area of research. Building on the success of the First Edition, this edition has been completely revised and updated to include the latest developments in the field.

Written in an accessible style, Medicinal Chemistry: An Introduction, Second Edition carefully explains fundamental principles, assuming little in the way of prior knowledge. The book focuses on the chemical principles used for drug discovery and design covering physiology and biology where relevant. It opens with a broad overview of the subject with subsequent chapters examining topics in greater depth.

From the reviews of the First Edition:

"It contains a wealth of information in a compact form" ANGEWANDTE CHEMIE, INTERNATIONAL EDITION

"Medicinal Chemistry is certainly a text I would chose to teach from for undergraduates. It fills a unique niche in the market place." PHYSICAL SCIENCES AND EDUCATIONAL REVIEWS

Leseprobe

Contents

Preface to the First Edition

Preface to the Second Edition

Acknowledgements

Abbreviations

1 An introduction to drugs, their action and discovery

1.1 Introduction

1.2 What are drugs and why do we need new ones?

1.3 Drug discovery and design: a historical, outline

1.4 Leads and analogues: some desirable properties

1.5 Sources of leads and drugs

1.6 Methods and routes of administration: the pharmaceutical phase

1.7 Introduction to drug action

1.8 Classification of drugs

1.9 Questions

2 Drug structure and solubility

2.1 Introduction

2.2 Structure

2.3 Stereochemistry and drug design

2.4 Solubility

2.5 Solutions

2.6 The importance of water solubility

2.7 Solubility and the structure of the solute

2.8 Salt formation

2.9 The incorporation of water solubilising groups in a structure

2.10 Formulation methods of improving water solubility

2.11 The effect of pH on the solubility of acidic and basic drugs

2.12 Partition

2.13 Surfactants and amphiphiles

2.14 Questions

3 Structure–activity and quantitative structure relationships

3.1 Introduction

3.2 Structure–activity relationship (SAR)

3.3 Changing size and shape

3.4 Introduction of new substituents

3.5 Changing the existing substituents of a lead

3.6 Case study: a SAR investigation to discover potent geminal bisphosphonates

3.7 Quantitative structure–activity relationship (QSAR)

3.8 Questions

4 Computer-aided drug design

4.1 Introduction

4.2 Molecular mechanics

4.3 Molecular dynamics

4.4 Quantum mechanics

4.5 Docking

4.6 Comparing three-dimensional structures by the use of overlays

4.7 Pharmacophores and some of their uses

4.8 Modelling protein structures

4.9 Three-dimensional QSAR

4.10 Other uses of computers in drug discovery

4.11 Questions

5 Combinatorial chemistry

5.1 Introduction

5.2 The solid support method

5.3 Encoding methods

5.4 Combinatorial synthesis in solution

5.5 Deconvolution

5.6 High-throughput screening (HTS)

5.7 Automatic methods of library generation and analysis

5.8 Questions

6 Drugs from natural sources

6.1 Introduction

6.2 Bioassays

6.3 Dereplication

6.4 Structural analysis of the isolated substance

6.5 Active compound development

6.6 Extraction procedures

6.7 Fractionation methods

6.8 Case history: the story of Taxol

6.9 Questions

7 Biological membranes

7.1 Introduction

7.2 The plasma membrane

7.3 The transfer of species through cell membranes

7.4 Drug action that affects the structure of cell membranes and walls

7.5 Questions

8 Receptors and messengers

8.1 Introduction

8.2 The chemical nature of the binding of ligands to receptors

8.3 Structure and classification of receptors

8.4 General mode of operation

8.5 Ligand-response relationships

8.6 Ligand-receptor theories

8.7 Drug action and design

8.8 Questions

9 Enzymes

9.1 Introduction

9.2 Classification and nomenclature

9.3 Active sites and catalytic action

9.4 Regulation of enzyme activity

9.5 The specific nature of enzyme action

9.6 The mechanisms of enzyme action

9.7 The general physical factors affecting enzyme action

9.8 Enzyme kinetics

9.9 Enzyme inhibitors

9.10 Transition state inhibitors

9.11 Enzymes and drug design: some general considerations

9.12 Examples of drugs used as enzyme inhibitors

9.13 Enzymes and drug resistance

9.14 Ribozymes

9.15 Questions

10 Nucleic acids

10.1 Introduction

10.2 Deoxyribonucleic acid (DNA)

10.3 The general functions of DNA

10.4 Genes

10.5 Replication

10.6 Ribonucleic acid (RNA)

10.7 Messenger RNA (mRNA)

10.8 Transfer RNA (tRNA)

10.9 Ribosomal RNA (rRNA)

10.10 Protein synthesis

10.11 Protein synthesis in prokaryotic and eukaryotic cells

10.12 Bacterial protein synthesis inhibitors (antimicrobials)

10.13 Drugs that target nucleic acids

10.14 Viruses

10.15 Recombinant DNA technology (genetic engineering)

10.16 Questions

11 Pharmacokinetics

11.1 Introduction

11.2 Drug concentration analysis and its therapeutic significance

11.3 Pharmacokinetic models

11.4 Intravascular administration

11.5 Extravascular administration

11.6 The use of pharmacokinetics in drug design

11.7 Extrapolation of animal experiments to humans

11.8 Questions

12 Drug metabolism

12.1 Introduction

12.2 Secondary pharmacological implications of metabolism

12.3 Sites of action

12.4 Phase I metabolic reactions

12.5 Examples of Phase I metabolic reactions

12.6 Phase II metabolic routes

12.7 Pharmacokinetics of metabolites

12.8 Drug metabolism and drug design

12.9 Prodrugs

12.10 Questions

13 Complexes and chelating agents

13.1 Introduction

13.2 The shapes and structures of complexes

13.3 Metal–ligand affinities

13.4 The general roles of metal complexes in biological processes

13.5 Therapeutic uses

13.6 Drug action and metal chelation

13.7 Questions

14 Nitric oxide

14.1 Introduction

14.2 The structure of nitric oxide

14.3 The chemical properties of nitric oxide

14.4 The cellular production and role of nitric oxide

14.5 The role of nitric oxide in physiological and pathophysiological states

14.6 Therapeutic possibilities

14.7 Questions

15 An introduction to drug and analogue synthesis

15.1 Introduction

15.2 Some general considerations

15.3 Asymmetry in syntheses

15.4 Designing organic syntheses

15.5 Partial organic synthesis of xenobiotics

15.6 Questions

16 Drug development and production

16.1 Introduction

16.2 Chemical development

16.3 Pharmacological and toxicological testing

16.4 Drug metabolism and pharmacokinetics

16.5 Formulation development

16.6 Production and quality control

16.7 Patent protection

16.8 Regulation

16.9 Questions

Selected further reading

Answers to questions

Index

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Library of Congress Cataloging-in-Publication Data

Thomas, Gareth, Dr.

Medicinal chemistry : an introduction / Gareth Thomas.–2nd ed.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-02597-0 (cloth : alk. paper)–ISBN 978-0-470-02598-7 (pbk. : alk. paper)

1. Pharmaceutical chemistry. I. Title.

[DNLM: 1. Chemistry, Pharmaceutical. 2. Drug Design. 3. Drug Evaluation. 4. Pharmacokinetics. QV 744 T4567m 2007]

RS403.T447 2007

615’.19-dc22

                   2007026412

Preface to the First Edition

This book is written for second, and subsequent, year undergraduates studying for degrees in medicinal chemistry, pharmaceutical chemistry, pharmacy, pharmacology and other related degrees. It assumes that the reader has a knowledge of chemistry at level one of a university life sciences degree. The text discusses the chemical principles used for drug discovery and design with relevant physiology and biology introduced as required. Readers do not need any previous knowledge of biological subjects.

Chapter 1 is intended to give an overview of the subject and also includes some topics of peripheral interest to medicinal chemists that are not discussed further in the text. Chapter 2 discusses the approaches used to discover and design drugs. The remaining chapters cover the major areas that have a direct bearing on the discovery and design of drugs. These chapters are arranged, as far as is possible, in a logical succession.

The approach to medicinal chemistry is kept as simple as possible. Each chapter has a summary of its contents in which the key words are printed in bold type. The text is also supported by a set of questions at the end of each chapter. Answers, sometimes in the form of references to sections of the book, are listed separately. A list of recommended further reading, classified according to subject, is also included.

Gareth Thomas

Preface to the Second Edition

This book is written for second and subsequent year undergraduates studying for degrees in medicinal chemistry, pharmaceutical chemistry, pharmacy, pharmacology and other related degrees. It assumes that the reader has a knowledge of chemistry at Level 1 of a university life science degree. The text discusses the chemical principles used for drug discovery and design with relevant physiology and biology introduced as required. Readers do not need any previous knowledge of biological subjects.

The second edition of Medicinal Chemistry, an Introduction has a new layout that I hope presents the subject in a more logical form. The main changes are that Chapter 2 has been rewritten as three separate chapters, namely, structure–activity and quantitative structure relationships, computer-aided drug design and combinatorial chemistry. Two new chapters entitled Drugs from Natural Sources and Drug Development and Production have been added. The text has been simplified and extended where appropriate with a number of case histories, new examples and topics. Among the new topics are a discussion of monoclonal antibodies and photodynamic drugs. The inclusion of the new chapters and new material has necessitated a reduction in the biological and chemical introductions to some topics and the omission of some material included in the first edition. Furthermore, the reader should be aware that there are many more drugs and targets than those discussed in this text.

Chapter 1 introduces and gives an overview of medicinal chemistry. This is followed by chapters that discuss the principal methods used in drug design and the isolation of drugs from natural sources. Chapters 7–14 are concerned with a discussion of more specialised aspects of medicinal chemistry. The final two chapters outline drug and analogue synthesis, development and production. Appropriate chapters have an outline introduction to the relevant biology. Each chapter is supported by a set of questions. Answers to these questions, sometimes in the form of references to sections and figures in the book, are listed separately. An updated list of further reading, classified according to subject, is also included.

Gareth Thomas

Acknowledgements

I wish to thank all my colleagues and students, past and present, whose help enabled this second edition of my book to be written. In particular I would like to rethank all those who helped me with the first edition. I would like particularly to thank the following for their help with the second edition: Dr L. Banting; Dr J. Brown for once again acting as my living pharmacology dictionary; Dr P. Cox for his advice on molecular modelling; Dr J. Gray for proofreading the sections on monoclonal antibodies; Dr P. Howard for bringing me up to date with advances in combinatorial chemistry and allowing me to use his lecture notes; Dr Tim Mason, Mr A. Barrow and Dr D. Brimage; Dr A. Sautreau for proofreading and correcting Chapter 6; Robin Usher and his colleagues at Mobile Library Link One for their help in obtaining research papers; Dr. G. White; and Professor D. Thurston for his support. My thanks are also due to Dr J. Fetzer of Tecan Deutschland GmbH, Crailsheim, Germany for the pictures of the equipment used in high-throughput screening. I also wish to acknowledge that the main source of the historical information given in the text is Drug Discovery, a History, by W. Sneader, published by John Wiley and Sons Ltd.

I would like to offer a very special thanks to the dedicated NHS medical teams who have treated my myeloma over the past years. Without their excellent care I would not have been here to have written this book. I would particularly like to thank Dr R. Corser, Dr T. Cranfield and the other doctors of the Haematology Department at the Queen Alexandra Hospital, Portsmouth, the nurses and ancillary staff of Ward D16, Queen Alexandra Hospital, Portsmouth, Dr K. Orchard, Dr C. Ottensmier and their respective staff at Southampton General Hospital and the nurses and ancillary staff of Wards C3 and C6 at Southampton General Hospital.

Finally, I would like to thank my wife for the cover design for the first Edition and the sketches included in this text. Her support through the years has been an essential contribution to my completing the text.

Abbreviations

AAdenineAbeAbequoseACAdenylate cyclaseACEAngiotensin-converting enzymesAChAcetyl cholineADAPTAntibody-directed abzyme prodrug therapyADEPTAntibody-directed enzyme prodrug therapyADMEAbsorption, distribution, metabolism and eliminationADRAdverse drug reactionAIDSAcquired immuno deficiency syndromeAlaAlanineAMPAdenosine monophosphateArgArginineAspAspartateATPAdenosine triphosphateAUCArea under the curveAZTZidovudineBALBritish anti-LewisiteBESODBovine erythrocyte superoxide dismutaseCCytosineCaMCalmodulincAMPCyclic adenosine monophosphateCbzN-(Benzyloxycarbonyloxy)succinamideClClearanceCNSCentral nervous systemCoACoenzyme ACoMFAComparative molecular field analysisCYP-450Cytochrome P-450 familyCysCysteineCxConcentration of xdATPDeoxyadenosine triphosphated.e.Diastereoisomeric excessDHFDihydrofolic acidDHFRDihydrofolate reductaseDMPKDrug metabolism and pharmacokineticsDNADeoxyribonucleic aciddTMPDeoxythymidylate-5′-monophosphatedUMPDeoxyuridylate-5′-monophosphateECEnzyme CommissionEDRFEndothelium-derived relaxing factorEDTAEthylenediaminotetraacetic acide.e.Enantiomeric excessELFEffluent load factorEMEAEuropean Medicines Evaluation AgencyEPCEuropean Patent ConventionEPOEuropean Patent OfficeEsTaft steric parameterFBioavailabilityFADFlavin adenine dinucleotideFDAFood and Drug Administration (USA)FdUMP5-Fluoro-2′-deoxyuridyline monophosphateFGIFunctional group interconversionfh4TetrahydrofolateFMOFlavin monooxygenasesFmoc9-Fluorenylmethoxychloroformyl groupFUdRP5-Fluoro-2′-deoxyuridylic acidGGuanineGABAγ-Aminobutyric acidGCGuanylyl cyclaseGDEPTGene-directed enzyme prodrug therapyGDPGuanosine diphosphateGIGastrointestinalGlnGlutamineGluGlutamatic acidGlyGlycine5′-GMPGuanosine 5′-monophosphateGSHGlutathioneGTPGuanosine triphosphateHAMAHuman anti-mouse antibodiesHbHaemoglobinHbSSickle cell haemoglobinHisHistidineHIVHuman immunodeficiency diseasehnRNAHeterogeneous nuclear RNAHTSHigh-throughput screeningIDDMInsulin-dependent diabetes mellitusIgImmunoglobinsIleIsoleucineip3Inositol-1,4,5-triphosphateIVIntravenousIMIntramuscularKDO2-Keto-3-deoxyoctanoatekxReaction rate constant for reaction xLDALithium diisopropylamideLDHLactose dehydrogenaseLeuLeucineLysLysineMA(A)Marketing authorisation (application)MabMonoclonal antibodymAChMuscarinic cholinergic receptorMAOMonoamine oxidaseMCAMedicines Control AgencyMESNA2-MercaptoethanesulphonateMetMethionineMOMolecular orbitalMoz4-Methoxybenzyloxychloroformyl groupMRMolar refractivitymRNAMessenger RNAnAChNicotinic cholinergic receptorNAD+Nicotinamide adenine dinucleotide (oxidised form)NADHNicotinamide adenine dinucleotide (reduced form)NADP+Nicotinamide dinucleotide phosphate (oxidised form)NADPHNicotinamide dinucleotide phosphate (reduced form)NAGβ-N-AcetylglucosamineNAMβ-N-Acetylmuramic acidNCINational Cancer Institute (USA)NOSNitric oxide synthaseP-450Cytochrome P-450 oxidasePABAp-Aminobenzoic acidPCTPatent Cooperation TreatyPDTPhotodynamic therapyPEGPolyethyene glycolPGProstaglandinPhePhenylalaninePOPeros (by mouth)pre-mRNAPremessenger RNAProProlineptRNAPrimary transcript RNAQSARQuantitative structure-activity relationshipQxRate of blood flow for xRMMRelative molecular massRNARibonucleic acidSSvedberg unitsSAMS-AdenosylmethionineSARStructure-activity relationshipSerSerineSIN-13-Morpholino-sydnomineTThymineTdRPDeoxythymidylic acidTHFTetrahydrofolic acidThrThreoninetRNATransfer RNATyrTyrosineUUracilUDPUridine diphosphateUDPGAUridine diphosphate glucuronic acidUdRPDeoxyuridylic acidValValineVdVolume of distributionWHOWorld Health Organization

1

An introduction to drugs, their action and discovery

1.1 Introduction

The primary objective of medicinal chemistry is the design and discovery of new compounds that are suitable for use as drugs. This process involves a team of workers from a wide range of disciplines such as chemistry, biology, biochemistry, pharmacology, mathematics, medicine and computing, amongst others.

The discovery or design of a new drug not only requires a discovery or design process but also the synthesis of the drug, a method of administration, the development of tests and procedures to establish how it operates in the body and a safety assessment. Drug discovery may also require fundamental research into the biological and chemical nature of the diseased state. These and other aspects of drug design and discovery require input from specialists in many other fields and so medicinal chemists need to have an outline knowledge of the relevant aspects of these fields.

1.2 What are drugs and why do we need new ones?

Drugs are strictly defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants. The activity of a drug is its pharmaceutical effect on the subject, for example, analgesic or β-blocker, whereas its potency is the quantitative nature of that effect. Unfortunately the term drug is also used by the media and the general public to describe the substances taken for their psychotic rather than medicinal effects. However, this does not mean that these substances cannot be used as drugs. Heroin, for example, is a very effective painkiller and is used as such in the form of diamorphine in terminal cancer cases.

Drugs act by interfering with biological processes, so no drug is completely safe. All drugs, including those non-prescription drugs such as aspirin and paracetamol (Fig. 1.1) that are commonly available over the counter, act as poisons if taken in excess. For example, overdoses of paracetamol can causes coma and death. Furthermore, in addition to their beneficial effects most drugs have non-beneficial biological effects. Aspirin, which is commonly used to alleviate headaches, can also cause gastric irritation and occult bleeding in some people The non-beneficial effects of some drugs, such as cocaine and heroin, are so undesirable that the use of these drugs has to be strictly controlled by legislation. These unwanted effects are commonly referred to as side effects. However, side effects are not always non-beneficial; the term also includes biological effects that are beneficial to the patient. For example, the antihistamine promethazine is licenced for the treatment of hayfever but also induces drowsiness, which may aid sleep.

Figure 1.1 Aspirin and paracetamol

Drug resistance or tolerance (tachyphylaxis) occurs when a drug is no longer effective in controlling a medical condition. It arises in people for a variety of reasons. For example, the effectiveness of barbiturates often decreases with repeated use because the body develops mixed function oxidases in the liver that metabolise the drug, which reduces its effectiveness. The development of an enzyme that metabolises the drug is a relatively common reason for drug resistance. Another general reason for drug resistance is the downregulation of receptors (see section 8.6.1). Downregulation occurs when repeated stimulation of areceptor results in the receptor being broken down. This results in the drug being less effective because there are fewer receptors available for it to act on. However, downregulating has been utilised therapeutically in a number of cases. The continuous use of gonadotrophin releasing factor, for example, causes gonadotrophin receptors that control the menstrual cycle to be downregulated. This is why gonadotrophin-like drugs are used as contraceptives. Drug resistance may also be due to the appearance of a significantly high proportion of drug-resistant strains of microorganisms. These strains arise naturally and can rapidly multiply and become the currently predominant strain of that microorganism. Antimalarial drugs are proving less effective because of an increase in the proportion of drug-resistant strains of the malaria parasite.

New drugs are constantly required to combat drug resistance even though it can be minimised by the correct use of medicines by patients. They are also required for improving the treatment of existing diseases, the treatment of newly identified diseases and the production of safer drugs by the reduction or removal of adverse side effects.