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Fundamentals of Medicinal Chemistry
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Fundamentals of
Medicinal Chemistry
Gareth Thomas
University of Portsmouth, UK
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Copyright
#
2003 by John Wiley & Sons Ltd,
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Library of Congress Cataloging-in-Publication Data
Thomas, Gareth, Dr.
Fundamentals of medicinal chemistry / Gareth Thomas.
p. cm.
Includes bibliographical references and index.
ISBN 0-470-84306-3 (cloth : alk. paper) ISBN 0-470-84307-1 (paper : alk. paper)
1. Pharmaceutical chemistry. I. Title.
RS403.T446 2003
615 ’ .19 — — dc21
2003014218
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN 0-470 84306 3 (Hardback)
ISBN 0-470 84307 1 (Paperback)
Typeset in 11/14pt Times by Kolam Information Services Pvt. Ltd, Pondicherry, India
Printed and bound in Great Britain by Antony Rowe Ltd
This book is printed on acid-free paper responsibly manufactured from sustainable forestry,
in which at least two trees are planted for each one used for paper production.
Contents
Preface
xi
Acknowledgements
xii
Abbreviations/Acronyms
xiii
1 Biological Molecules
1
1.1 Introduction
1
1.2 Amino acids
1
1.2.1 Introduction
1
1.2.2 Structure
3
1.2.3 Nomenclature
3
1.3 Peptides and proteins
4
1.3.1 Structure
6
1.4 Carbohydrates
10
1.4.1 The structure of monosaccharides
11
1.4.2 The nomenclature of monosaccharides
14
1.4.3 Glycosides
15
1.4.4 Polysaccharides
17
1.4.5 The nomenclature of polysaccharides
18
1.4.6 Naturally occurring polysaccharides
18
1.5 Lipids
20
1.5.1 Introduction
20
1.5.2 Fatty acids
20
1.5.3 Acylglycerols (glycerides)
21
1.5.4 Steroids
21
1.5.5 Terpenes
22
1.5.6 Phospholipids
23
1.5.7 Glycolipids
25
1.6 Nucleic acids
26
1.6.1 Introduction
26
1.6.2 DNA, structure and replication
28
1.6.3 Genes and the human genome project
30
1.6.4 RNA, structure and transcription
31
1.6.5 Classification and function of RNA
33
1.7 Questions
34
2 An Introduction to Drugs and their Action
37
2.2 What are drugs and why do we need new ones?
37
2.3 Drug discovery and design, a historical outline
39
2.4 Sources of drugs and lead compounds
43
2.1 Introduction
37
vi
CONTENTS
2.4.1 Natural sources
43
2.4.2 Drug synthesis
45
2.4.3 Market forces and ‘me-too drugs’
45
2.5 Classification of drugs
45
2.6 Routes of administration, the pharmaceutical phase
46
2.7 Introduction to drug action
49
2.7.1 The pharmacokinetic phase
49
Absorption
49
Distribution
50
Metabolism
51
Eliminination
51
2.7.2 Bioavailability of a drug
53
2.7.3 The pharmacodynamic phase
53
2.8 Questions
55
3 An Introduction to Drug Discovery
57
3.1 Introduction
57
3.2 Stereochemistry and drug design
59
3.2.1 Structurally rigid groups
59
3.2.2 Conformation
60
3.2.3 Configuration
60
3.3 Solubility and drug design
61
3.3.1 The importance of water solubility
62
3.4 Solubility and drug structure
63
3.5 Salt formation
64
3.6 The incorporation of water solubilizing groups in a structure
65
3.6.1 The type of group
66
3.6.2 Reversibly and irreversibly attached groups
66
3.6.3 The position of the water solubilizing group
67
3.6.4 Methods of introduction
67
3.7 Questions
70
4 The SAR and QSAR Approaches to Drug Design
71
4.1 Structure–activity relationships (SARs)
71
4.2 Changing size and shape
73
4.3 Introduction of new substituents
73
4.3.1 The introduction of a group in an unsubstituted
position
73
4.3.2 The introduction of a group by replacing an
existing group
76
4.4 Quantitative structure–activity relationships (QSARs)
78
4.4.1 Lipophilicity
79
Partition coefficients (P)
79
Lipophilic substitution constants ( p )
80
4.4.2 Electronic effects
82
The Hammett constant ( s )
82
4.4.3 Steric effects
83
The Taft steric parameter (E s )
84
Molar refractivity (MR)
84
Other parameters
85

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