An Introduction to Medicinal Chemistry

Graham L. Patrick
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An Introduction to Medicinal
Chemistry
Seventh Edition

Graham L. Patrick
Great Clarendon Street, Oxford, OX2 6DP, United Kingdom

Oxford University Press is a department of the University of Oxford. It furthers the

University’s objective of excellence in research, scholarship, and education by
publishing worldwide. Oxford is a registered trade mark of Oxford University Press
in the UK and in certain other countries

© Oxford University Press 2023

The moral rights of the author have been asserted

Fourth edition 2009

Fifth edition 2013
Sixth edition 2017

All rights reserved. No part of this publication may be reproduced, stored in a

retrieval system, or transmitted, in any form or by any means, without the prior
permission in writing of Oxford University Press, or as expressly permitted by law,
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organization. Enquiries concerning reproduction outside the scope of the above
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You must not circulate this work in any other form and you must impose this same
condition on any acquirer

Published in the United States of America by Oxford University Press

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Standard Edition ISBN 978–0–19–886666–4

International Edition ISBN 978–0–19–886943–6
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Printed in the UK by Bell & Bain Ltd., Glasgow

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Created on: 06 April 2023 at 12:00 p.m.

Preface

Graham L. Patrick

This text is aimed at undergraduates and postgraduates who have a

basic grounding in chemistry and are studying a module or degree in
medicinal chemistry. It attempts to convey, in a readable and
interesting style, an understanding about drug design and the
molecular mechanisms by which drugs act in the body. In so doing, it
highlights the importance of medicinal chemistry in all our lives and
the fascination of working in a field which overlaps the disciplines of
chemistry, biochemistry, physiology, microbiology, cell biology, and
pharmacology. Consequently, the book is of particular interest to
students who might be considering a future career in the
pharmaceutical industry.

Following the success of the first six editions, as well as useful

feedback from readers, there has been some reorganization and
updating of chapters, especially those in section E.

Following the introductory chapter, the book is divided into five

parts:
• Part A contains five chapters that cover the structure and
function of important drug targets such as receptors,
 enzymes, and nucleic acids. Students with a strong
background in biochemistry will already know this material
but may find these chapters a useful revision of the essential
points.

• Part B covers pharmacodynamics in Chapters 7–10 and

pharmacokinetics in Chapter 11. Pharmacodynamics is the
study of how drugs interact with their molecular targets, and
the consequences of those interactions. Pharmacokinetics
relates to the issues involved in a drug reaching its target in
the first place.

• Part C covers the general principles and strategies involved

in discovering and designing new drugs and developing
them for the marketplace.

• Part D looks at particular ‘tools of the trade’, which are

invaluable in drug design, that is, QSAR, combinatorial
synthesis, and in silico drug design.

• Part E covers a selection of specific topics within medicinal

chemistry—antibacterial, antiviral, and anticancer agents;
kinase inhibitors; antibodies; cholinergics and
anticholinesterases; adrenergics; opioid analgesics; antiulcer
agents; and cardiovascular agents.
To some extent, the chapters in Part E reflect the changing emphasis
in medicinal chemistry research. Antibacterial agents, cholinergics,
adrenergics, and opioids have long histories and much of the early
development of these drugs relied heavily on random variations of
lead compounds on a trial-and-error basis. This approach was
wasteful, but it led to the recognition of various design strategies
which could be used in a more rational approach to drug design. The
development of the antiulcer drug cimetidine (Chapter 27)
represents one of the early examples of the rational approach to
medicinal chemistry. However, the real revolution in drug design
resulted from giant advances made in molecular biology and genetics
which have provided a detailed understanding of drug targets and
how they function at the molecular level. This, allied to the use of
molecular modelling and X-ray crystallography, has revolutionized
drug design. The development of protease inhibitors as antiviral
agents (Chapter 20), kinase inhibitors as anticancer agents (Chapter
22) and the statins as cholesterol-lowering agents (Case study 1) are
prime examples of the modern approach.

G. L. P.
March 2022
About the Book

Graham L. Patrick

An Introduction to Medicinal Chemistry, Seventh Edition and its

accompanying companion website contain many learning features.
This section illustrates each of these learning features and explains
how they will help you to understand this fascinating subject.

Emboldened key words

Terminology is emboldened and defined in a glossary at the end of

the book to help you to become familiar with the language of
medicinal chemistry.

Boxes

Boxes are used to present in-depth material and to explore how the
concepts of medicinal chemistry are applied in practice.
Key points

Summaries at the end of major sections within chapters highlight

and summarize key concepts and provide a basis for revision.

Struggle Alert

Extra information provided online for specific subjects to support

particularly complex topics.

If you are looking for extra support in this topic go to the Online
Learning Link.

Questions

Questions appear at the end of each chapter so you can test your
understanding and apply the concepts presented in the chapter.
Further reading

Selected references allow you to easily research those topics that are
of particular interest to you.

Appendix and glossary

The appendix includes an index of drug names and their

corresponding trade names. There is also an extensive glossary.

Links

Links added to the text alert the reader to relevant articles and
molecular modelling exercises on the accompanying website for the
textbook. In the seventh edition, alerts are provided to exercises that
allow the reader to make use of the Protein Data Bank to study the
interactions of various drugs with their target binding site.
Disclaimer

Brand names are given for the convenience of readers, but these are
examples and we have not attempted to include all possible brands
About Oxford Learning Link

Graham L. Patrick

Oxford Learning Link provide students and lecturers with ready-to-

use teaching and learning resources. They are free of charge,
designed to complement the textbook, and offer additional materials
that are suited to electronic delivery.

All these resources can be downloaded and are fully customizable.

This allows them to be incorporated into your institution’s existing
virtual learning environment.

You will find this material at:

www.learninglink.oup.com/access/patrick-7e-
introduction-medicinal-chemistry
Student resources

Multiple choice questions

Self-test multiple choice questions are available for each chapter.
These questions allow you to test your knowledge and grasp of key
concepts as you progress through the book. Each question is
submitted online, which provides you with an immediate mark and
instant feedback.
Rotatable 3D structures
JPEG and Chem3D versions of selected molecules in the book help
you to visualize molecules. Full instructions and link to free software
are provided.

Web articles
A series of articles placed on the web allows you to read further into
selected topics. Links in the textbook alert you to the existence of
these articles.

Molecular modelling
A series of molecular modelling exercises added to the website are
for students using Spartan or Chem3D molecular modelling
software. Alerts are provided in the textbook to molecular modelling
exercises related to specific topic areas.

Protein Data Bank

A new feature for the seventh edition involves exercises that allow
the reader to make use of the Protein Data Bank to study the
interactions of various drugs with their target binding site.
Lecturer resources

Test Bank
The test bank provides multiple choice questions that can be
downloaded and customized for your teaching.

Answers
Answers to end-of-chapter questions.

Figures from the book

All of the figures from the textbook are available to download
electronically for use in lectures and handouts.

PowerPoint slides
PowerPoint slides are provided to help teach selected topics from the
book.
Acknowledgements

The author and Oxford University Press thank the following people,
who have given advice on the various editions of this textbook:
Dr Lee Banting, School of Pharmacy and Biomedical
Sciences, University of Portsmouth, UK
Dr Don Green, Department of Health and Human Sciences,
London Metropolitan University, UK

Dr Mike Southern, Department of Chemistry, Trinity

College, University of Dublin, Ireland
Dr Mikael Elofsson (Assistant Professor), Department of
Chemistry, Umeå University, Sweden
Dr Ed Moret, Faculty of Pharmaceutical Sciences, Utrecht
University, The Netherlands
Professor John Nielsen, Department of Natural Sciences,
Royal Veterinary and Agricultural University, Denmark
Professor H. Timmerman, Department of Medicinal
Chemistry, Vrije Universiteit, Amsterdam, The Netherlands
Professor Nouri Neamati, School of Pharmacy, University of
Southern California, USA

Professor Kristina Luthman, Department of Chemistry,

Gothenburg University, Sweden
Professor Taleb Altel, College of Pharmacy, University of
Sharjah, United Arab Emirates

Professor Dirk Rijkers, Faculty of Pharmaceutical Sciences,

Utrecht University, The Netherlands

Dr Sushama Dandekar, Department of Chemistry,

University of North Texas, USA

Dr John Spencer, Department of Chemistry, School of Life

Sciences, University of Sussex, UK

Dr Angeline Kanagasooriam, School of Physical Sciences,

University of Kent at Canterbury, UK

Dr A Ganesan, School of Chemistry, University of

Southampton, UK

Dr Rachel Dickens, Department of Chemistry, University of

Durham, UK

Dr Gerd Wagner, School of Chemical Sciences and

Pharmacy, University of East Anglia, UK

Dr Colin Fishwick, School of Chemistry, University of Leeds,

UK

Professor Paul O’Neil, Department of Chemistry, University

of Liverpool, UK

Professor Trond Ulven, Department of Chemistry,

University of Southern Denmark, Denmark

Professor Jennifer Powers, Department of Chemistry and

Biochemistry, Kennesaw State University, USA
 Professor Joanne Kehlbeck, Department of Chemistry,
Union College, USA

Dr Robert Sindelar, Faculty of Pharmaceutical Sciences,

University of British Columbia, Canada

Professor John Carran, Department of Chemistry, Queen’s

University, Canada

Professor Anne Johnson, Department of Chemistry and

Biology, Ryerson University, Canada

Dr Jane Hanrahan, Faculty of Pharmacy, University of

Sydney, Australia

Dr Ethel Forbes, School of Science, University of West of

Scotland.

The author expresses his gratitude to Dr John Spencer of the

University of Sussex for co-authoring Chapter 16, the preparation of
several web articles, and for feedback during the preparation of this
and previous editions. Much appreciation is due to Nahoum Anthony
and Dr Rachel Clark of the Strathclyde Institute for Pharmaceutical
and Biomedical Sciences at the University of Strathclyde, for their
assistance with creating Figures 2.9, B.8.2.1, B.8.2.3, 17.9, 17.44,
20.15, 20.22, 20.54, and 20.55 from PDB files, some of which were
obtained from the RSCB Protein Data Bank. Dr James Keeler of the
Department of Chemistry, University of Cambridge kindly generated
the molecular models that appear on the book’s Online Resource
Centre. Thanks also to Dr Stephen Bromidge of GlaxoSmithKline for
permitting the description of his work on selective 5-HT2C
antagonists, and for providing many of the diagrams for that web
article. Finally, many thanks to Cambridge Scientific, Oxford
Molecular, and Tripos for their advice and assistance in the writing
of Chapter 17.
Detailed contents

1 Drugs and drug targets: an overview

1.1 What is a drug?

1.2 Drug targets

1.2.1 Cell structure

1.2.2 Drug targets at the molecular level

1.3 Intermolecular bonding forces

1.3.1 Electrostatic or ionic bonds

1.3.2 Hydrogen bonds

1.3.2.1 Conventional hydrogen bonds

1.3.2.2 Unconventional hydrogen bonds

1.3.3 Van der Waals interactions

1.3.4 Dipole–dipole, ion–dipole, and cation–π interactions

1.3.5 π–π interactions

1.3.6 Halogen bonds

1.3.7 Repulsive interactions

1.3.8 The role of water and hydrophobic interactions

1.4 Pharmacokinetic issues and medicines

1.5 Classification of drugs

1.5.1 By pharmacological effect

 1.5.2 By chemical structure

1.5.3 By target system

1.5.4 By target molecule

1.6 Naming of drugs and medicines

Part A Drug targets: structure and function

2 Protein structure and function
2.1 The primary structure of proteins

2.2 The secondary structure of proteins

2.2.1 The α-helix

2.2.2 The β-pleated sheet

2.2.3 The β-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

3.5 The catalytic role of enzymes

3.5.1 Binding interactions

3.5.2 Acid/base catalysis

3.5.3 Nucleophilic groups

3.5.4 Stabilization of the transition state

3.5.5 Cofactors

3.5.6 Naming and classification of enzymes

3.5.7 Genetic polymorphism and enzymes

3.6 Regulation of enzymes

3.7 Isozymes

3.8 Enzyme kinetics

3.8.1 The Michaelis–Menten equation

 3.8.2 Lineweaver–Burk plots

◼ 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

4.5 How does the binding site change shape?

4.6 Ion channel receptors

4.6.1 General principles

4.6.2 Structure

4.6.3 Gating

4.6.4 Ligand-gated and voltage-gated ion channels

4.7 G-Protein-coupled receptors

4.7.1 General principles

4.7.2 Structure of G-protein-coupled receptors

4.7.3 The rhodopsin-like family of G-protein-coupled receptors

4.7.4 Dimerization of G-coupled receptors

4.8 Kinase receptors

4.8.1 General principles

4.8.2 Structure of tyrosine kinase receptors

4.8.3 Activation mechanism for tyrosine kinase receptors

 4.8.4 Tyrosine kinase receptors as targets in drug discovery

4.8.4.1 The ErbB family of tyrosine kinase receptors

4.8.4.2 Vascular endothelial growth factor receptors

4.8.4.3 Platelet-derived growth factor receptors

4.8.4.4 Stem cell growth factor receptors

4.8.4.5 Anaplastic lymphoma kinase

4.8.4.6 The RET receptor

4.8.4.7 Hepatocyte growth factor receptor or c-MET receptor

4.9 Intracellular receptors

4.10 Regulation of receptor activity

4.11 Genetic polymorphism and receptors

5 Receptors and signal transduction

5.1 Signal transduction pathways for G-protein-coupled receptors (GPCRs)

5.1.1 Interaction of the receptor–ligand complex with G-proteins

5.1.2 Signal transduction pathways involving the α-subunit

5.2 Signal transduction involving G-proteins and adenylate cyclase

5.2.1 Activation of adenylate cyclase by the αs-subunit

5.2.2 Activation of protein kinase A

5.2.3 The Gi-protein

5.2.4 General points about the signalling cascade involving cyclic AMP

5.2.5 The role of the βγ-dimer

5.2.6 Phosphorylation
 5.3 Signal transduction involving G-proteins and phospholipase Cβ

5.3.1 G-Protein effect on phospholipase Cβ

5.3.2 Action of the secondary messenger: diacylglycerol

5.3.3 Action of the secondary messenger: inositol triphosphate

5.3.4 Resynthesis of phosphatidylinositol diphosphate

5.4 The role of β-arrestins in modulating the activity of G-protein-coupled

receptors

5.5 Signal transduction involving kinase receptors

5.5.1 Activation of signalling proteins and enzymes

5.5.2 The MAPK signal transduction pathway

5.5.3 Activation of guanylate cyclase by kinase receptors

5.5.4 The JAK-STAT signal transduction pathway

5.5.5 The PI3K/Akt/mTOR signal transduction pathway

5.6 The hedgehog signalling pathway

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

Part B Pharmacodynamics and

pharmacokinetics
7 Enzymes as drug targets
7.1 Inhibitors acting at the active site of an enzyme

7.1.1 Reversible inhibitors

7.1.2 Irreversible inhibitors

7.2 Inhibitors acting at allosteric binding sites

7.3 Uncompetitive and non-competitive inhibitors

7.4 Transition-state analogues: renin inhibitors

7.5 Suicide substrates

7.6 Isozyme selectivity of inhibitors

7.7 Medicinal uses of enzyme inhibitors

7.7.1 Enzyme inhibitors used against microorganisms

7.7.2 Enzyme inhibitors used against viruses

7.7.3 Enzyme inhibitors used against the body’s own enzymes

 7.7.4 Enzyme modulators

7.8 Enzyme kinetics

7.8.1 Lineweaver–Burk plots

7.8.2 Comparison of inhibitors

◼ BOX 7 . 1 A cure for antifreeze poisoning

◼ BOX 7 . 2 Irreversible inhibition for the treatment of obesity

◼ BOX 7 . 3 Suicide substrates

◼ BOX 7 . 4 Designing drugs to be isozyme selective

◼ BOX 7 . 5 Action of toxins on enzymes

◼ BOX 7 . 6 Kinase inhibitors

8 Receptors as drug targets

8.1 Introduction

8.2 The design of agonists

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 outside the binding site

8.4 Partial agonists

8.5 Inverse agonists

8.6 Desensitization and sensitization

8.7 Tolerance and dependence

8.8 Receptor types and subtypes

8.9 Affinity, efficacy, and potency

◼ BOX 8 . 1 An unexpected agonist

◼ BOX 8 . 2 Estradiol and the estrogen receptor

9 Nucleic acids as drug targets

9.1 Intercalating drugs acting on DNA

9.2 Topoisomerase poisons: non-intercalating

9.3 Alkylating and metallating agents

9.3.1 Nitrogen mustards

9.3.2 Nitrosoureas

9.3.3 Busulfan

9.3.4 Cisplatin

9.3.5 Dacarbazine and procarbazine

9.3.6 Mitomycin C

9.4 Chain cutters

9.5 Chain terminators

9.6 Control of gene transcription

 9.7 Agents that act on RNA

9.7.1 Agents that bind to ribosomes

9.7.2 Antisense therapy

10 Miscellaneous drug targets

10.1 Transport proteins as drug targets

10.2 Structural proteins as drug targets

10.2.1 Viral structural proteins as drug targets

10.2.2 Tubulin as a drug target

10.2.2.1 Agents that inhibit tubulin polymerization

10.2.2.2 Agents that inhibit tubulin depolymerization

10.3 Biosynthetic building blocks as drug targets

10.4 Biosynthetic processes as drug targets: chain terminators

10.5 Protein–protein interactions

10.5.1 Inhibition of protein–protein interactions

10.5.2 Promotion of protein–protein interactions

10.6 Lipids as a drug target

10.6.1 ‘Tunnelling molecules’

10.6.2 Ion carriers

10.6.3 Tethers and anchors

10.7 Carbohydrates as drug targets

10.7.1 Glycomics

10.7.2 Antigens and antibodies

Another random document with
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overtaking him, we make comfortably sure that religion lends itself as
deftly as journalism to the light-hearted drolleries of the cruel.
Novelists, who understand how easy a thing it is to gratify our
humorous susceptibilities, venture upon doubtful jests. Mr.
Tarkington knows very well that the spectacle of a boy dismembering
an insect calls for reprobation; but that if the boy’s experiments can
be described as “infringing upon the domain of Dr. Carrell,” they
make a bid for laughter. “Penrod’s efforts—with the aid of a pin—to
effect a transference of living organism were unsuccessful; but he
convinced himself forever that a spider cannot walk with a beetle’s
legs.” It is funny to those who relish the fun. If it does not, as Mr.
Pater advises, make suffering ridiculous, it makes sympathy
ridiculous, as being a thing more serious than the occasion warrants.
The reader who is not amused tries to forget the incident, and
hurries cheerfully on.
A more finished example of callous gaiety, and one which has
been more widely appreciated, may be found in a story called
“Crocker’s Hole,” by Blackmore. It tells how a young man named
Pike, whom “Providence” had created for angling (the author is
comfortably sure on this point), caught an old and wary trout by the
help of a new and seductive bait. The over-wrought, over-coloured
beauty of Blackmore’s style is in accord with his highly sophisticated
sense of humour:
“The lover of the rose knows well a gay, voluptuous beetle, whose
pleasure it is to lie embedded in a fount of beauty. Deep among the
incurving petals of the blushing fragrance he loses himself in his joys
till a breezy waft reveals him. And when the sunlight breaks upon his
luscious dissipation, few would have the heart to oust such a gem
from such a setting. All his back is emerald sparkles; all his front, red
Indian gold, and here and there he grows white spots to save the
eye from aching. Pike slipped in his finger, fetched him out, and gave
him a little change of joys by putting a Limerick hook through his
thorax, and bringing it out between his elytra. Cetonia aurata liked it
not, but pawed the air very naturally, fluttered his wings, and trod
prettily upon the water under a lively vibration. He looked quite as
happy, and considerably more active than when he had been cradled
in the anthers of a rose.”
The story is an angling story, and it would be unreasonable to spoil
it by sympathizing with the bait. But there is something in the
painting of the little beetle’s beauty, and in the amused description of
its pain, which would sicken a donkey-beating costermonger, if he
were cultivated enough to know what the author was driving at. It
takes education and an unswerving reverence for sport to save us
from the costermonger’s point of view.
There are times when it is easier to mock than to pity; there are
occasions when we may be seduced from blame, even if we are not
won all the way to approval. Mrs. Pennell tells us in her very
interesting and very candid life of Whistler that the artist gratified a
grudge against his Venetian landlady by angling for her goldfish
(placed temptingly on a ledge beneath his window-sill); that he
caught them, fried them, and dropped them dexterously back into
their bowl. It is a highly illustrative anecdote, and we are more
amused than we have any business to be. Mr. Whistler’s method of
revenge was the method of the Irish tenants who hocked their
landlord’s cattle; but the adroitness of his malice, and the whimsical
picture it presents, disarms sober criticism. A sympathetic setting for
such an episode would have been a comedy played in the streets of
Mantua, under the gay rule of Francesco Gonzaga, and before the
eyes of that fair Isabella d’Este who bore tranquilly the misfortunes of
others.
We hear so much about the sanitary qualities of laughter, we have
been taught so seriously the gospel of amusement, that any writer,
preacher, or lecturer, whose smile is broad enough to be infectious,
finds himself a prophet in the market-place. Laughter, we are told,
freshens our exhausted spirits and disposes us to good-will,—which
is true. It is also true that laughter quiets our uneasy scruples and
disposes us to simple savagery. Whatever we laugh at, we condone,
and the echo of man’s malicious merriment rings pitilessly through
the centuries. Humour which has no scorn, wit which has no sting,
jests which have no victim, these are not the pleasantries which
have provoked mirth, or fed the comic sense of a conventionalized
rather than a civilized world. “Our being,” says Montaigne, “is
cemented with sickly qualities; and whoever should divest man of the
seeds of those qualities would destroy the fundamental conditions of
life.”

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