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An Introduction to Medicinal Chemistry
7th Edition 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
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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
4.7.2 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
4.8.2 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

10.7.3 Cyclodextrins
◼ BOX 1 0 . 1 Antidepressant drugs acting on transport proteins
◼ BOX 1 0 . 2 Targeting transcription factor–coactivator

interactions
◼ BOX 1 0 . 3 Cyclodextrins as drug scavengers
11 Pharmacokinetics and related topics

11.1 The three phases of drug action
11.2 A typical journey for an orally active drug
11.3 Drug absorption
11.4 Drug distribution
11.4.1 Distribution round the blood supply
11.4.2 Distribution to tissues
11.4.3 Distribution to cells
11.4.4 Other distribution factors
11.4.5 Blood–brain barrier
11.4.6 Placental barrier
11.4.7 Drug–drug interactions
11.5 Drug metabolism
11.5.1 Phase I and phase II metabolism
11.5.2 Phase I transformations catalysed by cytochrome P450 enzymes
11.5.3 Phase I transformations catalysed by flavin-containing

monooxygenases
11.5.4 Phase I transformations catalysed by other enzymes

11.5.5 Phase II transformations
11.5.6 Metabolic stability
11.5.7 The first pass effect
11.6 Drug excretion
11.7 Drug administration
11.7.1 Oral administration
11.7.2 Absorption through mucous membranes
11.7.3 Rectal administration
11.7.4 Topical administration
11.7.5 Inhalation
11.7.6 Injection
11.7.7 Implants
11.8 Drug dosing
11.8.1 Drug half-life
11.8.2 Steady state concentration
11.8.3 Drug tolerance
11.8.4 Bioavailability
11.9 Formulation
11.10 Drug delivery
◼ BOX 1 1 . 1 Metabolism of an antiviral agent
◼ CASE S T U D Y 1 Statins
Part C Drug discovery, design, and
development
Drug discovery, design, and development: the past
Drug discovery, design, and development: the present
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
12.2.3 Target specificity and selectivity between species
12.2.4 Target specificity and selectivity within the body
12.2.5 Targeting drugs to specific organs and tissues
12.2.6 Pitfalls
12.2.7 Multi-target drugs
12.3 Identifying a bioassay
12.3.1 Choice of bioassay
12.3.2 In vitro tests
12.3.3 In vivo tests
12.3.4 Test validity
12.3.5 High-throughput screening
12.3.6 Screening by NMR
12.3.7 Affinity screening

12.3.8 Surface plasmon resonance
12.3.9 Scintillation proximity assay
12.3.10 Isothermal titration calorimetry
12.3.11 Virtual screening
12.4 Finding a lead compound
12.4.1 Screening of natural products
12.4.1.1 The plant kingdom
12.4.1.2 Microorganisms
12.4.1.3 Marine sources
12.4.1.4 Animal sources
12.4.1.5 Venoms and toxins
12.4.2 Medical folklore
12.4.3 Screening synthetic compound ‘libraries’
12.4.4 Existing drugs
12.4.4.1 ‘Me too’ and ‘me better’ drugs
12.4.4.2 Enhancing a side effect
12.4.5 Starting from the natural ligand or modulator
12.4.5.1 Natural ligands for receptors
12.4.5.2 Natural substrates for enzymes
12.4.5.3 Enzyme products as lead compounds
12.4.5.4 Natural modulators as lead compounds
12.4.6 Combinatorial and parallel synthesis

12.4.7 Computer-aided design of lead compounds
12.4.8 Serendipity and the prepared mind
12.4.9 Computerized searching of structural databases
12.4.10 Fragment-based lead discovery
12.4.11 Properties of lead compounds
12.5 Isolation and purification
12.6 Structure determination
12.7 Herbal medicine
◼ BOX 1 2 . 1 Recently discovered targets: the caspases
◼ BOX 1 2 . 2 Pitfalls in choosing particular targets
◼ BOX 1 2 . 3 Early tests for potential toxicity
◼ BOX 1 2 . 4 Selective optimization of side activities (SOSA)
◼ BOX 1 2 . 5 Natural ligands as lead compounds
◼ BOX 1 2 . 6 Examples of serendipity
◼ BOX 1 2 . 7 The use of NMR spectroscopy in finding lead

compounds
◼ BOX 1 2 . 8 Click chemistry in situ
◼ BOX 1 2 . 9 Fragment-based design of a scaffold using X-ray

crystallography
13 Drug design: optimizing target interactions

13.1 Structure–activity relationships
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 Binding role of ketones and aldehydes
13.1.5 Binding role of amines
13.1.6 Binding role of amides
13.1.7 Binding role of quaternary ammonium salts
13.1.8 Binding role of carboxylic acids
13.1.9 Binding role of esters
13.1.10 Binding role of alkyl and aryl halides
13.1.11 Binding role of thiols and ethers
13.1.12 Binding role of phosphates, phosphonates, and phosphinates
13.1.13 Binding role of other functional groups
13.1.14 Binding role of alkyl groups and the carbon skeleton
13.1.15 Binding role of heterocycles
13.1.16 Isosteres
13.1.17 Testing procedures
13.1.18 SAR in drug optimization
13.2 Identification of a pharmacophore
13.3 Drug optimization: strategies in drug design
13.3.1 Variation of substituents
13.3.1.1 Alkyl substituents
13.3.1.2 Substituents on aromatic or heteroaromatic rings
13.3.1.3 Varying substituents to change the pKa of ionizable groups

13.3.1.4 Synergistic effects
13.3.2 Extension of the structure
13.3.3 Chain extension/contraction
13.3.4 Ring expansion/contraction
13.3.5 Ring variations
13.3.6 Ring fusions
13.3.7 Isosteres and bio-isosteres
13.3.8 Simplification of the structure
13.3.9 Rigidification of the structure
13.3.10 Conformational blockers
13.3.11 Rigidification through intramolecular bonds
13.3.12 Structure-based drug design and molecular modelling
13.3.13 Drug design by NMR spectroscopy
13.3.14 The elements of luck and inspiration
13.3.15 Designing drugs to interact with more than one target
13.3.15.1 Agents designed from known drugs
13.3.15.2 Agents designed from non-selective lead compounds
13.4 Selectivity
13.5 Pharmacokinetics
◼ BOX 1 3 . 1 Converting an enzyme substrate to an inhibitor by

extension tactics
◼ BOX 1 3 . 2 Simplification
◼ BOX 1 3 . 3 Rigidification tactics in drug design
◼ BOX 1 3 . 4 The structure-based drug design of crizotinib
14 Drug design: optimizing access to the target

14.1 Optimizing hydrophilic/hydrophobic properties
14.1.1 Masking polar functional groups to decrease polarity
14.1.2 Adding or removing polar functional groups to vary polarity
14.1.3 Varying hydrophobic substituents to vary polarity
14.1.4 Variation of N-alkyl substituents to vary pKa
14.1.5 Other structural variations affecting pKa
14.1.6 Bio-isosteres for polar groups involved in binding interactions
14.2 Making drugs more resistant to chemical and enzymatic degradation
14.2.1 Steric shields
14.2.2 Electronic effects of bio-isosteres and substituents
14.2.3 Steric and electronic modifications
14.2.4 Metabolic blockers
14.2.5 Removal or replacement of susceptible metabolic groups
14.2.6 Group shifts
14.2.7 Ring variation and ring substituents
14.3 Making drugs less resistant to drug metabolism
14.3.1 Introducing metabolically susceptible groups
14.3.2 Self-destruct drugs
14.4 Targeting drugs

14.4.1 Targeting tumour cells: ‘search and destroy’ drugs
14.4.2 Targeting gastrointestinal infections
14.4.3 Targeting peripheral regions rather than the central nervous

system
14.4.4 Targeting with membrane tethers
14.4.5 Targeting antibacterial agents using siderophores
14.5 Reducing toxicity
14.6 Prodrugs
14.6.1 Prodrugs to improve membrane permeability
14.6.1.1 Esters as prodrugs
14.6.1.2 N-Methylated prodrugs
14.6.1.3 Trojan horse approach for transport proteins
14.6.2 Prodrugs to prolong drug activity
14.6.3 Prodrugs masking drug toxicity and side effects
14.6.4 Prodrugs to lower water solubility
14.6.5 Prodrugs to improve water solubility
14.6.6 Prodrugs used in the targeting of drugs
14.6.7 Prodrugs to increase chemical stability
14.6.8 Prodrugs activated by external influence (sleeping agents)
14.7 Drug alliances
14.7.1 ‘Sentry’ drugs
14.7.2 Localizing a drug’s area of activity

14.7.3 Increasing absorption
14.8 Endogenous compounds as drugs
14.8.1 Neurotransmitters
14.8.2 Natural hormones, peptides, and proteins as drugs
14.9 Peptides and peptidomimetics in drug design
14.9.1 Peptidomimetics
14.9.2 Peptide drugs
14.10 Oligonucleotides as drugs
◼ BOX 1 4 . 1 The use of bio-isosteres to increase absorption
◼ BOX 1 4 . 2 Shortening the lifetime of a drug
◼ BOX 1 4 . 3 Identifying and replacing potentially toxic groups
◼ BOX 1 4 . 4 Varying esters in prodrugs
◼ BOX 1 4 . 5 Prodrugs masking toxicity and side effects
◼ BOX 1 4 . 6 Prodrugs to improve water solubility
15 Getting the drug to market

15.1 Preclinical and clinical trials
15.1.1 Toxicity testing
15.1.2 Drug metabolism studies
15.1.3 Pharmacology, formulation, and stability tests
15.1.4 Clinical trials
15.1.4.1 Phase I studies
15.1.4.2 Phase II studies

15.1.4.3 Phase III studies
15.1.4.4 Phase IV studies
15.1.4.5 Ethical issues
15.2 Patenting and regulatory affairs
15.2.1 Patents
15.2.2 Regulatory affairs
15.2.2.1 The regulatory process
15.2.2.2 Fast-tracking and orphan drugs
15.2.2.3 Good laboratory, manufacturing, and clinical practice
15.2.2.4 Cost-versus-benefit analysis
15.3 Chemical and process development
15.3.1 Chemical development
15.3.2 Process development
15.3.3 Choice of drug candidate
15.3.4 Natural products
◼ BOX 1 5 . 1 Drug metabolism studies and drug design
◼ BOX 1 5 . 2 Synthesis of ebalzotan
◼ BOX 1 5 . 3 Synthesis of ICI D7114
◼ CASE S T U D Y 2 The design of ACE inhibitors
◼ CASE S T U D Y 3 Artemisinin and related antimalarial drugs
◼ CASE S T U D Y 4 The design of oxamniquine
◼ CASE S T U D Y 5 Fosmidomycin as an antimalarial agent

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 1 6 . 1 Examples of scaffolds
◼ BOX 1 6 . 2 Dynamic combinatorial synthesis of vancomycin

dimers
17 In silico drug design

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
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
17.11 3D pharmacophore identification
17.11.1 X-ray crystallography
17.11.2 Structural comparison of active compounds
17.11.3 Automatic identification of pharmacophores
17.12 Docking procedures
17.12.1 Manual docking
17.12.2 Automatic docking
17.12.3 Defining the molecular surface of a binding site

17.12.4 Rigid docking by shape complementarity
17.12.5 The use of grids in docking programs
17.12.6 Rigid docking by matching hydrogen-bonding groups
17.12.7 Rigid docking of flexible ligands: the FLOG program
17.12.8 Docking of flexible ligands: anchor and grow programs
17.12.8.1 Directed Dock and Dock 4.0
17.12.8.2 FlexX
17.12.8.3 The Hammerhead program
17.12.9 Docking of flexible ligands: simulated annealing and genetic

algorithms
17.13 Automated screening of databases for lead compounds and drug

design
17.14 Protein mapping
17.14.1 Constructing a model protein: homology modelling
17.14.2 Constructing a binding site: hypothetical pseudoreceptors
17.15 De novo drug design
17.15.1 General principles of de novo drug design
17.15.2 Automated de novo drug design
17.15.2.1 LUDI
17.15.2.2 SPROUT
17.15.2.3 LEGEND
17.15.2.4 GROW, ALLEGROW, and SYNOPSIS
17.16 Planning compound libraries

17.17 Database handling
◼ BOX 1 7 . 1 Energy minimization of apomorphine
◼ BOX 1 7 . 2 Study of HOMO and LUMO orbitals
◼ BOX 1 7 . 3 Finding conformations of cyclic structures by

molecular dynamics
◼ BOX 1 7 . 4 Identification of an active conformation
◼ BOX 1 7 . 5 Constructing a receptor map
◼ BOX 1 7 . 6 Designing a non-steroidal glucocorticoid agonist
18 Quantitative structure–activity relationships (QSAR)

18.1 Graphs and equations
18.2 Physicochemical properties
18.2.1 Hydrophobicity
18.2.1.1 The partition coefficient (P)
18.2.1.2 The substituent hydrophobicity constant (π)
18.2.1.3 P versus π
18.2.2 Electronic effects
18.2.3 Steric factors
18.2.3.1 Taft’s steric factor (Es)
18.2.3.2 Molar refractivity
18.2.3.3 Verloop steric parameter
18.2.4 Other physicochemical parameters
18.3 Hansch equation

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rescue, and had not the Horse Guards opportunely fell in upon them, as they lay
battering before my house, it had not been in my power to have prevented a further
mischief.” (Letter from Humphrey Weld to the Earl of Craven in Calendar of State
Papers, Domestic, 1671, pp. 241–2).
478. Historical MSS. Commission, Duke of Portland’s MSS., Report XIII.,
App. 1, 683.
479. He was certainly there in April of that year. “Letter for the French
Ambassador brought by a sea captain enclosed to Humphrey Wield, at his house in
Wield Street, London.” (Calendar of State Papers, Domestic, 1673, p. 166).
480. For example: (i) 10 March 1676–7. Information of William Herriot that
“at Nieuport he met Captains Douglas and Ennys, who desired him to make his
address to the Spanish Ambassador at London, who lived at Wild House.”
(Calendar of State Papers, Domestic, 1677–8, p. 14); (ii.) 29 March, 1679. Lord
Clarendon reports that “in Mr. Weld’s garden in a grotto are 27 chests of goods....
Mr. Bedloe present said they belonged to Don Pedro de Ronquillio who was
present at the search and would not admit to have the letters perused.” (Historical
MSS. Commission, House of Lords MSS., App. to 11th Report, Part II., pp. 126–7);
(iii.) 26 April, 1681. Evelyn records his visit to “Don Pietro Ronquillio’s, the
Spanish Ambassador, at Wild House”; (iv.) 9th September, 1686. “The Spanish
Ambassador made a bonfire at Wild House last night and brought out wine for the
mob, but the rabble overthrew the bonfires, broke the cask of wine and broke the
windows, and pulled down some of the brick wall.” (Historical MSS. Commission,
Duke of Portland’s MSS., III., p. 397).
481. See Petition and Appeal of Ralph Lister, MSS. of House of Lords, New
Series, IV., pp. 274–5.
482. 21st December, 1693. “The Spanish Ambassador has taken a house in the
Old Spring Garden, where the Duke of Norfolk lately lived, and has, in a manner,
fitted up his chapel. Notice was sent to his Excellency that for some reasons a
Romish chapel could not be permitted within the verge of the Court, so he is
removing back to Weld House.” (Calendar of State Papers, Domestic, 1693, p.
433).
“Weld House is to be Lett, containing 33 Rooms, Garrets and Cellars, with
other suitable conveniences, in Weld Street near L.I. Fields. Enquire at Weld
House, or at Marybone House.” (London Gazette, Sep. 13–17, 1694).
483. Reproduced here.
484. Indenture between Isaac Foxcroft and others and Hugh Jones (in
possession of the London County Council).
486. Close Roll, 5 Chas. I. (2800)—Indenture between Richard Holford and
Sir Edward Stradling, reciting the earlier indenture.
487. See p. 93.
488. Chancery Proceedings, Bridges, 465–184. Plea of John Corrance.
490. Middlesex Feet of Fines, 32 Eliz., Hilary.
491. Ibid., 21 Jas. I., Easter.
492. Recited in Indenture between Matthew Francis and Symond Harborne,
in the possession of the London County Council.
493. Lease by the Rt. Hon. Lord Cary to William Loringe, in the possession of
the London County Council.
494. See p. 112.
495. Katherine Clifton, only daughter and heiress of Gervase, Lord Clifton of
Leighton Bromswold.
496. Calendar State Papers, Domestic, 1623–5, p. 488; 1627–8, p. 10; 1628–
9, p. 359; 1629–31, p. 38.
497. Ibid., 1628–9, p. 369.
498. Somerset House Wills, Harvey, 6 (Proved 15th January, 1638–9).
499. Lady Elizabeth Cust’s The Brownlows of Belton (Records of the Cust
Family Series), II., p. 61.
500. This is not quite certain, but there does not seem much doubt that the
entry refers to Lennox House.
501. The two portions were subsequently assessed for the Hearth Tax at 26
and 11 hearths respectively. The whole house was therefore comparable in size with
Bristol House, assessed at 40 hearths.
502. The Countess of Dysart writes from “Lady Allington’s house, Drury
Lane,” on 22nd August, 1667 (Calendar State Papers, Domestic, 1667, p. 409), and
in November, 1668 or 1669, Lord Allington refers to his mother’s house in Drury
Lane (Ibid., 1668–9, p. 55). Lady Allington was succeeded in this house by Lady
Ivey (Hearth Tax Roll for 1675).
503. Somerset House Wills, Batt, 136. (Proved, with 39 codicils, 28th June,
1680).
504. Middlesex Registry Memorials, 1716, III., 24.
505. Parton states that Brownlow Street appears in the parish books in 1685.
506. Indenture of 28th April, 1722, between Gilbert Umfreville and Chas.
Umfreville and Ric. Baker (Middlesex Registry Memorials, 1722, VI., 85).
507. See p. 105.
508. Grey’s St. Giles’s of the Lepers, pp. 114–5.
510. See p. 103.
511. Parton’s Hospital and Parish of St. Giles, p. 125.
512. The ratebooks from 1730 (earliest extant) to 1746 show “Daniel Hahn,”
possibly a more correct form of the name, at this house.
513. Indenture dated 27th May, 1728, between Peter Walter and Nicholas
Lovell (Middlesex Registry Memorials, 1728, VI., 15).
514. Grey’s St. Giles’s of the Lepers, p. 116.
516. Close Roll, 12 William III. (4863)—Indenture between (1) Mary
Rawlinson, (2) Giles Powell and (3) Jeremiah Ridge.
517. See p. 109.
518. See p. 112.
519. Privy Council Register, Vol. 29, p. 424.
520. Calendar State Papers, Domestic, 1611–18, p. 551.
521. Ibid., p. 555.
524. It is just possible that a later reference to the spring is to be found in the
petition dated 7th July, 1637, of the inhabitants of the Old Town of St. Giles,
“complayning of ye stopping up of a fair large and open well in ye said towne; being
of great use and comfort to ye peters who now find ye want thereof in these times of
contagion, ye same being continued to bee stopped up as aforesaid, by ye now
landlord Frauncis Garrett.” (Privy Council Register, Vol. 48, p. 105).
526. Close Roll, 9 Eliz. (742).
527. Close Roll, 24 Eliz. (1129)—Indenture between Jas. Briscowe, Joan his
wife and John Wise and Jas. Mascall.
528. Close Roll, 11 Chas. I. (3057).—Indenture between Thos. and Olive
Godman and Francis and Frances Gerard.
529. Property on the east side of Drury Lane and on the north side of Broad
Street is mixed up with this, and it is not possible entirely to separate them.
530. “... abutting east on a court called Ragged Staffe Court (which court was
heretofore in the possession of John Vavasour.” (Close Roll, 12 William III. (4863)
—Indenture between Mary Rawlinson, etc., cited above).
531. Parton’s statement that the two were identical (Hospital and Parish of St.
Giles, p. 127) is incorrect. The Hearth Tax Rolls mention both, and both are clearly
shown in the map accompanying Strype’s edition of Stow (Plate 5).
532. He died in 1585 (Inquisitiones Post Mortem, Series II., Vol. 208 (173).)
533. John Vavasour’s will (Somerset House Wills, Winderbanck, 65), was
proved on 18th June, 1608.
534. Close Roll, 9 Eliz., (749).
535. Middlesex Registry Memorials, 1723, V., 181–2.
536. On 16th January, 1717–8, Edward Theedham leased to Chas. Hall and
Ant. Elmes The Bear Brewhouse, in St. Giles (Middlesex Registry Memorials, 1717,
IV., 263).
537. Ancient tavern signs were nearly always “on the hoop,” which seems to
have originated “in the highly ornamented bush or crown, which latterly was made
of hoops covered with evergreens.” (Larwood and Hotton, History of Signboards,
p. 504.)
538. Hospital and Parish of St. Giles, p. 237.
539. Close Roll, 31 Chas. II. (4527).
540. Sewer Rate Book for that year.
543. On 27th March, 1573, Henry Amptill and Roger Mascall, brewers, were
convicted of having set at large certain suspected persons, whom William Westone,
a “hedborowe” of St. Giles, had taken in a certain tenement of the said Henry
Amptill and had imprisoned. (Middlesex County Records, Sessions Rolls, I., p. 82).
544. In 1621, John Ampthill was granted leave to alienate 5 messuages, 11
cottages and 4 gardens to Anne, Robert, James and Thomas Foote (Patent Roll, 19
Jas. I. (2263)); in 1614 he sold 3 houses to Richard Windell (Middlesex Feet of
Fines, 12 Jas I., Mich.), whose grandson in 1630 parted with them to Abraham
Hawkins (Close Roll, 6 Chas. I. (2823)); and in 1625 he obtained leave to alienate
14 messauges to John and Abraham Hawkins. On the death of Abraham in 1645,
he was still in possession of 14 messuages in St. Giles (Inquisitiones Post Mortem,
2nd Series, 707 (41).)
545. The Hawkins property seems to have descended to Sir William Dawes,
Archbishop of York, whose mother was Jane Hawkins. By a deed of 1726
(Middlesex Registry Memorials, 1726, IV., 389) Jane Lewis sold the remainder of
a lease granted by Sir William, and comprising inter alia a house which by
reference to the ratebooks can be shown to be the second westwards from Lamb
Alley.
546. Close Roll, 7 Chas. I. (2895).
547. Close Roll, 1655 (3866).
548. On 3rd December, 1603, William Barber, of St. Giles, gardener, was
convicted, with others, of throwing filth and dung near the highway in a certain
close called “Blumsberrie fieldes.” (Middlesex County Records, Sessions Rolls, II.,
p. 4).
549. Middlesex Feet of Fines, 32 Eliz., Easter.
551. Sale by Arthur Blythe to William Wigg and Thomas Whitfield, in trust for
John Smallbone, dated 1680, and quoted by Parton (op. cit.) p. 126.
552. See p. 106.
554. Hospital and Parish of St. Giles, p. 113. Newlands was actually in the
parish of St. Marylebone (see p. 125).
555. Blemundsbury, p. 308.
556. “Maslyn’s Pond” and “Maslyn Fields” are mentioned in the parish books
in 1644 and 1656 (Parton’s Hospital and Parish of St. Giles, pp. 270–1).
557. See p. 101.
558. See Sale by Arthur Blythe to Wigg and Whitfield, quoted by Parton
(Hospital and Parish of St. Giles, p. 126).
559. Kingsford’s edition, II., p. 91.
561. See p. 123. The Close had a reputed area of 10 acres (See e.g., Rents of
Henry VIII. in London and the Suburbs, 35 Henry VIII. (Rentals and Surveys,
General Series), Roll 452).
562. Parliamentary Survey (Augmentation Office), Middlesex, 24.
563. I.e., the field called Long Acre or Elm Field, lying between Castle Street
and the street called Long Acre.
564. Obviously a mistake for “south”; Castle Street is the thoroughfare meant.
565. Monmouth Street, now Shaftesbury Avenue, and West Street.
566. I.e., The Bowl property, see p. 110.
567. Sir John Brownlow. The same variation occurs in the Hearth Tax Rolls.
568. Close Roll, 2 Geo. II. (5363).
569. Endowed Charities, County of London, Vol. V., p. 946.
570. Patent Roll, 24 Charles II. (3137).
571. The existence of a “Tower Street” between King Street and White Lion
Street is impossible. A portion of the close was in 1690 used as a laystall (Calendar
of State Papers, Domestic, 1689–90, p. 389).
572. Chancery Proceedings, Bridges, 36–47. Suit of Jas. Kendricke.
573. Chancery Proceedings, Bridges, 614–105. Suit of William Jennens.
574. There are records inter alia of (a) four houses built in Great St. Andrew
Street, between Michaelmas, 1693, and August, 1694 (Middlesex Registry
Memorials, 1734, V., 266), and (b) houses built in Monmouth Street and Little Earl
Street in July, 1693, and October, 1694 (Chancery Decree Roll, 1933. Suit of
William Lloyd).
575. The leases of many of the houses erected on the south-west of the close do
not seem to have been granted before 1708–9.
576. Notes and Queries, 11th Series, VIII., pp. 182–3.
577. The plan is probably a little later than 1691 (the date assigned to it), for,
as has been shown, Neale did not obtain his lease until 1693.
578. Wheatley and Cunningham’s London Past and Present, III., p. 234.
580. Recited in Indenture of 25th October, 1728, between Jas. Joye (1), Oliver
Martin and Thos. Russell (2) and Rev. Thos. Blackwell (3) (Close Roll, 2 Geo. II.
(5364)).
581. Much of the above information is taken from Emily Dibdin’s Seven Dials
Mission: the story of the old Huguenot Church of All Saints, West Street.
583. It should be mentioned, however, that in a petition, probably belonging
to the year 1354, the Mayor and Commonalty of London claimed that the Hospital
had been founded by a citizen of London suffering from leprosy. (Calendar of
Letterbooks of the City of London, Letterbook G., p. 27).
584. Parton (History of the Hospital and Parish of St. Giles-in-the-Fields, p.
1) and, following him, Dugdale (Monasticon VII., p. 635) give the date of the
Hospital’s foundation as 1101. This is certainly wrong. Parton’s authority was an
entry in Leland’s Collectanea, I., p. 418 (2nd edn.), which under the date 1101
mentions several events, (i.) Henry’s marriage with Maud, (ii.) his appointment of
a military guard for his brother Robert who was in prison, (iii.) Maud’s foundation
of the Hospital of St. Giles. The next entry is dated 1109. The date 1101 is obviously
only intended to cover (i.) (which took place strictly speaking in 1100), for Robert
was not taken prisoner until the battle of Tinchebray in 1106. The passage
therefore would seem to suggest a date between 1106 and 1109 for the foundation
of St. Giles.
585. Survey of London (Kingsford’s edn.), II., p. 90.
586. Historia Anglicana, p. 176b.
587. Parton in his transcription of the document reads “forty” throughout, and
has been copied by everybody. It is, however, clearly “quatuordecim” in all cases.
588. Ancient Petitions, E. 617.
589. Ancient Petitions, E. 617; 2448.
590. Calendar of Letterbooks of the City of London, Letterbook G., p. 28.
591. Ibid., p. 29.
592. I.e., 27 Edw. I. (Calendar of Patent Rolls, p. 404). It has been generally
assumed that the date was 1354, i.e., 27 Edw. III., no doubt because Parton
(Hospital and Parish of St. Giles, pp. 23, 26) when translating the document
relating to the suit between the Abbot of St. Mary Graces and the Master of Burton
Lazars gave the name of the King as Edward the son of Edward, whereas the
reading is clearly “Edward the son of Henry.”
593. It really extended somewhat to the west of the eastern side of the modern
road, which has been formed by widening the ancient Hog Lane.
594. Close Roll, 16 James I. (2384).—Indenture, dated 19 March, 1617–8,
between Robert Lloyd and Isaac Bringhurst.
595. See p. 124.
596. Inquisitiones Post Mortem, 3 Edward VI. (89).
597. Close Roll, 8 Elizabeth (722).
598. Close Roll, 8 James I. (2066)—Indenture, dated 20th February, 1610–11,
between John Graunge and Robert Lloyd.
599. A sixth was sold in 1622 by John and William Flood to Zachery Bethel,
lying to the south of Sir Edward Fisher’s house, but this seems to have only
recently been built on land taken out of the four acres (see p. 122).
600. Close Roll, 16 James I. (2384).
601. The reversion was then sold to Francis Ashburnham (Close Roll, 5
Charles I. (2800)—Indenture, dated 1st March, 1628–9, between John Stafey and
Isaac Bringhurst and The Worshipful Francis Ashburnham).
602. Endowed Charities (County of London), Vol. III. (1900), p. 348.
603. Close Roll, 10 James I. (2123)—Indenture between Robert Floyd and
William Holt and John Harman.
604. Close Roll, 1652 (3683)—Indenture between John Hooker and Walter
Bigg.
605. Letter dated 5th May, 1677, from Philip, Lord Wharton to Sir R. Verney
(Historical MSS. Commission, Verney MSS., App. to VII. Report, p. 469).
606. Parton’s Hospital and Parish of St. Giles-in-the-Fields, p. 117.
607. Middlesex Registry Memorials, 1727, VI., 138.
608. Close Roll, 16 James I. (2384)—Indenture between Robert Lloyd and
Isaac Bringhurst.
610. Close Roll, 7 Charles I. (2895)—Indenture between Anne Bringhurst and
John Stafey and the Lady Alice Dudley.
611. Close Roll, 10 Charles I. (3017).
612. Chancery Proceedings, Bridges, 455–66.—Suit of John Boswell.
613. The boundaries are given as (E) tenement now in occupation of Nicholas
Holden; (W) churchyard; (N) Kilburn to Holborn Highway; (S) orchard of Nicholas
Holden (Close Roll, 9 Elizabeth (742)—Indenture between Lord Mountjoy and
Percival Rowland).
614. The boundaries are given as: (S) highway from St. Giles to Knightsbridge;
(W) a tenement late of Rowland Percival, and a close of John Graunge; (N)
highway through St. Giles to Uxbridge (Close Roll, 11 Elizabeth (797)—Indenture
between Lord Mountjoy and Edward Kyngston).
615. See p. 125.
616. Inquisitiones Post Mortem, II. Series, Vol. 139 (134).
617. Inquisitiones Post Mortem, II. Series, Vol. 384 (139).
618. Recovery Roll, 21 James I. Trinity.—Indenture between John and
William Flood, and Zachery Bethel.
619. Somerset House Wills, Gee, 159.
620. Patent Roll, 23 Charles II. (3125).
621. Augmentation Office, Deed of Sale, E. 19. The Master of Burton Lazars
apparently lost by the transaction, but from a letter, dated 1st April, 1535, written
by Richard Layton to Cromwell, it would seem that at one time there was a distinct
prospect of his faring still worse. “I sent for the Master of Burton Lazer as you
desired, advertising him of the King’s pleasure commanding him to be here by
Easter eve, and desire you to intercede for him with the King that he might obtain
other lands for his lands of St. Giles’s. He came, and I have been with him divers
times. I have persuaded him to put his sole trust in you and that he shall not go to
the King in anywise before you bring him to His Grace. He is content to do so.
When you wish that I should bring him unto you to make further declaration to
him of the King’s pleasure, let me know.” (Calendar of Letters of Henry VIII., 26
H. VIII., p. 168).
622. These were in St. Anne’s, Soho.
623. After the Duke of Norfolk had heard that Legh was scheming to get the
mastership, he wrote that Legh was married, adding, “Alas! what pity it were that
such a vicious man should have the governance of that honest house!” (Letters and
Papers of Henry VIII., XII., i., p. 282).
624. Patent Roll, 28 Henry VIII. (671).
625. The whole of the above information is obtained from Chancery Decree
Roll (1).
626. Abstracts of Inquisitiones Post Mortem relating to the City of London,
ed. Geo. S. Fry, Part I., p. 62. Legh was buried in the old church of St. Leonard,
Shoreditch, and an illustration of his effigy is given in Ellis’s Antiquities of
Shoreditch. The following inscription was underneath (Hatton’s New View of
London, 1908):—
“Here under lye the Ashes and the Bones

Of Sir Tho. Leigh, that good and learned Knight,
Whose hasty Death, alas, the Godly still bemoan,
Tho his Soul always rejoice in God’s sight,
Great was his Wisdom, and greater was his Wit,
His Visage comely, with no sad Change dismay’d,
A Man in all Affairs a King to serve most fit,
Had not Death so soon his mortal Life betray’d.”
627. Chancery Decree Roll, No. 3.

628. Close Roll, 37 Henry VIII. (444).
629. This was in the parish of Edmonton, now Southgate.
630. On the north side of Broad Street, now in the parish of St. George,
Bloomsbury.
631. The Great Close of Bloomsbury and Wilkinson’s Close.
632. I.e., Middle Row (see Close Roll, 12 Elizabeth (832).—Indenture between
Lord and Lady Mountjoy and William Perye), formerly standing just outside
Holborn Bars.
633. These were in St. Marylebone. The Inquisition on the death of Sir John
Grange (1611) refers to “a close of land commonly known by the name of
Newlondes containing 24 acres, and ... all that parcel of land or lane (“venelle”)
near adjoining the aforesaid close ... situated within the parish of Marylebone.”
(Inquisitiones Post Mortem, II. Series, Vol. 686 (113)).
634. Licence to alienate granted 6th July, 1546.
635. Inquisitiones Post Mortem, II. Series, 3 Edward VI. (89).
636. Inquisitiones Post Mortem, 15 Elizabeth, Vol. 165, on Thomas Carew.
637. Ibid., 6 Elizabeth, Vol. 139.
638. Ibid., Series II. (49), Vol. 109.
639. Her second husband was Sir Thomas Chaloner.
640. According to the Dictionary of National Biography, he “spent the
fortune of his family in the pursuit of alchemy.”
641. The “Lorde Mountjoye and the Lady Katherine” are mentioned in a
mortgage by the former to John Mery, dated 1st February, 1556–7. (Close Roll, 4
and 5, Philip and Mary (547)).
643. Considerable doubt seems to have existed on this point. Side by side with
assertions to the contrary, there are plain statements that the mortgage was
redeemed (see e.g., Chancery Decree Roll, 54, concerning a complaint by Jas.
Mascall against Thomas Harrys and others). Nevertheless it is quite certain that
the statement in the text is true, for (1) the recognisance accompanying the
mortgage is not cancelled; (2) Blount’s son Charles (afterwards Earl of Devonshire)
definitely stated that the manor was not redeemed (Chancery Proceedings,
Elizabeth B. 15–52), suit of Charles Blount; (3) the steps by which the manor
descended from the Brownes are known.
644. Close Roll, 21 Eliz. (1059); Common Plea Roll, 25 Eliz., Hilary, 4010;
Close Roll, 34 Eliz. (1425). Parton (Hospital and Parish of St. Giles-in-the-Fields,
p. 331) bridges over the gap between Blount and Cope by the supposition that the
manor came into the hands of the last-named in consequence of a mortgage to one
“Master Cope, citizen of London.” But (1) the mortgage is not of the manor of St.
Giles, and (2) the proper reading is not “Cope” but “Rope.”
645. He was knighted on 20th April, 1603.
646. Close Roll, 14 Jas. I. (2308)—Indenture between Sir Henry Rich, Dame
Isabella, and Dame Dorothy Cope and Gifford and Risley.
647. Vestry Minutes, 1624–1719.
648. See p. 1.
649. Newcourt, op. cit., p. 612.
650. The sketch given by Parton, Hospital and Parish of St. Giles-in-the-
Fields, p. 54, is quite untrustworthy, and is in conflict with the little that is known
of the church. He gives no authority for the sketch save that it was as “preserved in
rude delineations of it, made near the time.”
652. Ibid., pp. 191–2.
653. Vestry Minutes, 1624–1719, f. 4.
654. A Mirrour of Christianity and a Miracle of Charity, etc., by R. B. [i.e.,
Robert Boreman], p. 121.
655. A New View of London (1708), I., p. 259.
656. Strype’s edition of Stow, 1720, II., pp. 77ff. The greater portion of what
follows is taken from Strype’s description.
657. See illustrations on map in Strype’s edition of Stow (Plate 5).
658. A list of Lady Dudley’s benefactions comprises the following: “She gave to
the Church of St. Giles, the greatest bell in the steeple; and divers great pieces of
massive plate; paved the chancel with marble, built the fair blue gate at the
entrance to the churchyard, and purchased a fair house of £30 a year value for the
perpetual incumbent. She also gave the hangings for the choir, which cost £80
10s., 2 service books, embroidered in gold, £5; velvet altar cloth with gold fringe
£60; a cambric cloth to lay over it with a deep bone lace £4 10s.; another fine
damask cloth £3; 2 cushions for the altar, richly embroidered with gold, £10; a
Turkey carpet to lay before the altar £6; a long screen to sever the chancel from the
church, richly carved and gilt, £200; a fair organ £100; the organ loft richly
wrought and gilt, and a tablet of the Ten Commandments, the Creed and Lord’s
Prayer, richly adorned, £80; the rails before the altar curiously carved and gilt,
£40.” (Calendar of State Papers, Domestic, 1668–9, p. 176).
659. Parton’s Hospital and Parish of St. Giles-in-the-Fields, pp. 200–1.
660. 4 Geo. I., cap. 14.
661. 3 Geo. II., cap. 19.
663. Hatton’s New View of London (1708), p. 262.
664. Parton’s Hospital and Parish of St. Giles, p. 224
665. Parton’s Hospital and Parish of St. Giles-in-the-Fields, pp. 216–7.
666. Novum Repertorium Ecclesiasticum Parochiale Londinense, p. 173.
668. See p. 123.
672. See p. 1.
673. Close Roll, 30 Henry VI.—Grant, dated 2nd April, 1452, by Jo. Crouton
and W. Horn to Jo. and Katherine Nayler.
674. To the east of Church Close.
676. History of London, p. 1363.
677. Tyburn Gallows (published by the London County Council), p. 16.
678. The gallows in St. Giles Fields erected for the execution of Lord Cobham
were obviously put up for that special purpose. There may, of course, have been a
manorial gallows, but no mention of such for St. Giles occurs in the Quo Warranto
Rolls.
679. Endowed Charities, County of London, III., p. 350.
681. Chancery Decree Roll, No. 3.
682. Inquisitiones Post Mortem, II. Series, Middlesex, Vol. 200 (5).
683. Formerly on the east side of Dyott Street, just outside the parish
boundary.
684. Close Roll, 9 Elizabeth (742).
685. Close Roll, 8 Charles I. (2946).
686. Close Roll, 1649 (31). Indenture, dated 20th March, 1648–9, between
John Barber als Grigg and Henry Baynbrigge.
687. Hospital and Parish of St. Giles-in-the-Fields, p. 152.
688. Edmund Buckeridge and Henry Loveday querentes: and Jane
Baynbrigge, widow; William Maynard and Mary, his wife; Nicholas Buckeridge,
and Sara, his wife; and Simon Dyott and Jane, his wife, deforciantes; of 100
messuages, 200 cottages, 40 gardens and 10 acres of land in St. Giles, Mary, Sara
and Jane renounce for their heirs. It will be seen that the property had grown, and
it is known that Bainbridge had purchased more (see e.g., purchase from Sir John
Bramston and others, Middlesex Feet of Fines, 1665, Trinity).
689. “The Rookery,” was a triangular space bounded by Bainbridge, George,
and High Streets; it was one dense mass of houses, through which curved narrow
tortuous lanes, from which again diverged close courts—one great mass, as if the
houses had originally been one block of stone, eaten by slugs into numberless
small chambers and connecting passages. The lanes were thronged with loiterers;
and stagnant gutters, and piles of garbage and filth infested the air. In the
windows, wisps of straw, old hats, and lumps of bed-tick or brown paper,
alternated with shivered panes of broken glass, the walls were the colour of
bleached soot, and doors fell from their hinges and worm-eaten posts. Many of the
windows announced, “Lodgings at 3d. a night,” where the wild wanderers from
town to town held their nightly revels.” (Timbs’ Curiosities of London (1867), p.
378.)
690. Opened in 1847.
691. Except perhaps the extreme east.
692. Wheatley and Cunningham (London, Past and Present) give the date of
the street’s formation as approximately 1670.
693. Memoirs of the Life and Works of Sir Christopher Wren (1823), p. 522.
694. Collins’s Peerage of England, 5th Edition, III., p. 328.
695. Memoirs of the Life and Works of Sir Christopher Wren, p. 522.
696. Burke’s Peerage.
698. Dictionary of National Biography.
699. Walpole’s Letters (Toynbee Edn.) XI., p. 52.
700. Survey of London, Vol. III., pp. 88–89.
701. Parish ratebooks.
703. Information kindly supplied by His Grace the Duke of Bedford.
704. Richardson and Gill’s London Houses from 1660 to 1820, p. 67.
705. A. E. Richardson’s Monumental Classic Architecture in Great Britain
and Ireland.
706. Survey of London, Vol. III. (St. Giles-in-the-Fields, Part I.), p. 108.
707. Beresford Chancellor’s History of the Squares of London, pp. 202–10.
709. Middlesex Registry Memorials, 1778, II., 409.
711. In the Parish of St. George, Bloomsbury.
712. Painted Decoration—the Georgian Period, by Ingleson C. Goodison
(Architectural Review, January, 1913).
713. Information kindly supplied by the Rev. Lewis Gilbertson, M.A., F.S.A.
720. Middlesex Registry Memorials, 1778, IV., 505.
723. Middlesex Registry Memorials, 1778, IV., 505.
724. See p. 153.
725. Boyle’s Court Guide, however, shows him at the house from 1796 to 1799.
726. The Dictionary of National Biography says that it was at No. 11, Bedford
Square.
728. Partly in the Parish of St. Giles-in-the-Fields and partly in that of St.
George, Bloomsbury.
731. See p. 151.
732. See pp. 84–5.
737. See p. 168.
739. Middlesex Registry Memorials, 1777, VII., 263.
745. Middlesex Registry Memorials, VI., 631.
749. Dictionary of National Biography.
761. Middlesex Registry Memorials, 1777, I., 637.
766. Middlesex Registry Memorials, 1777, I., 631.
769. See licence to alienate granted in Patent Roll, 9 Elizabeth (1038).
770. See p. 125.
771. See pardon for alienation granted in Patent Roll, 30 Elizabeth (1321).
772. Information kindly supplied by the City of London Corporation.
773. A. E. Richardson’s Monumental Classic Architecture.
774. A copy is in the County Hall collection.
775. It was the last of several designs prepared for a Select Committee of the
House of Commons who engaged in deliberating on the improvements to the Port,
including a new London Bridge. The view shows two bridges of six arches each,
with a drawbridge in the centre intended for the passage of ships. Between the
bridges flights of steps lead down to the river. The two large areas beyond the
bridges are terminated by crescents. The Monument stands in the chord of the
northern crescent, and a large obelisk in that of the southern.
776. Inquisitiones Post Mortem, Chas. I. (765), 37.
777. John Holles, first Earl of Clare (1564?–1637).
778. It seems probable that the land in question (which, being partly in St.
Giles and partly in St. Pancras, was described sometimes as in one parish,
sometimes in the other) is identical with the land in St. Pancras sold, together with
Clement’s Inn, by Sir William Hawte to William (afterwards Sir William) Holles,
ancestor of the Earls of Clare, in 1532 (Middlesex Feet of Fines, 23 Henry VIII.,
Hil.).
779. The boundary between St. Giles and St. Pancras used to run through the
middle of the close.
781. The Old Farm House in Tottenham Court Road, by Ambrose Heal.
TRANSCRIBER’S NOTES
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An Introduction To Medicinal Chemistry 7Th Edition Graham L Patrick Full Chapter

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An Introduction to Medicinal Chemistry

7th Edition Graham L. Patrick

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

© Oxford University Press 2023

The moral rights of the author have been asserted

Fourth edition 2009

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

Published in the United States of America by Oxford University Press

British Library Cataloguing in Publication Data

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

Printed in the UK by Bell & Bain Ltd., Glasgow

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

This text is aimed at undergraduates and postgraduates who have a

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

Following the introductory chapter, the book is divided into five

• Part B covers pharmacodynamics in Chapters 7–10 and

• Part C covers the general principles and strategies involved

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

• Part E covers a selection of specific topics within medicinal

An Introduction to Medicinal Chemistry, Seventh Edition and its

Emboldened key words

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

Summaries at the end of major sections within chapters highlight

Extra information provided online for specific subjects to support

Appendix and glossary

The appendix includes an index of drug names and their

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Multiple choice questions

Protein Data Bank

Figures from the book

Dr Mike Southern, Department of Chemistry, Trinity

Professor Kristina Luthman, Department of Chemistry,

Professor Dirk Rijkers, Faculty of Pharmaceutical Sciences,

Dr Sushama Dandekar, Department of Chemistry,

Dr John Spencer, Department of Chemistry, School of Life

Dr Angeline Kanagasooriam, School of Physical Sciences,

Dr A Ganesan, School of Chemistry, University of

Dr Rachel Dickens, Department of Chemistry, University of

Dr Gerd Wagner, School of Chemical Sciences and

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

Professor Paul O’Neil, Department of Chemistry, University

Professor Trond Ulven, Department of Chemistry,

Professor Jennifer Powers, Department of Chemistry and

Dr Robert Sindelar, Faculty of Pharmaceutical Sciences,

Professor John Carran, Department of Chemistry, Queen’s

Professor Anne Johnson, Department of Chemistry and

Dr Jane Hanrahan, Faculty of Pharmacy, University of

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

The author expresses his gratitude to Dr John Spencer of the

1 Drugs and drug targets: an overview

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