The handbook of medicinal chemistry : principles and practice

788 Pages·2015·44.424 MB·English

by  Davis, Andrew M., Ward, Simon Edward

The Handbook of Medicinal Chemistry
Principles and Practice
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The Handbook of Medicinal Chemistry
Principles and Practice
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36- Edited by
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82 Andrew Davis
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8 AstraZeneca, Mo¨lndal, Sweden
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1 Simon E Ward
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or Email: [email protected]
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d o AcataloguerecordforthisbookisavailablefromtheBritishLibrary
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blis rTheRoyalSocietyofChemistry2015
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Allrightsreserved
Apartfromfairdealingforthepurposesofresearchfornon-commercialpurposesorforprivatestudy,criticismor
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83 Preface
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03 Medicinal Chemistry sits at the heart of the pharmaceutical industry and the medicinal
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0. chemist has one of the most challenging and rewarding jobs imaginable. The medicinal
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oi: chemist designs the drug which must balance often conflicting demands of a suitable dose,
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g | by the chosen delivery route, at a desired dose frequency to provide a therapeutic effect while
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c. maintaining margins to adverse effects throughout the dosing period. The drug molecule
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s.r may be given to millions of patients all of whom may respond to the drug differently, and all
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p of whom must be treated safely and effectively. Whilst drug discovery is undoubtedly an en-
p:// deavour involving a wide range of scientific disciplines, the medicinal chemists are critical to
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n the design and progression of a drug molecule. It is the medicinal chemist who integrates
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4 and balances the diverse inputs into a single chemical structure which has the potential to
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2 become a new medicine.
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b This is an enormously difficult task. Our advances insynthetic organic chemistry mean that
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0n 0 pounddesignisfarhardertocontrol andrequiresextensiveexperienceandknowledgetotake
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d the sometimes subjective decisions to arrive at a potential drug candidate. There are few uni-
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s versal rules in drug design, and barely any universally accepted guidelines, and it sometimes
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u seems success is more a matter of chance. But, as Louis Pasteur said, ‘‘chance favours the
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prepared mind’’. However, given the current challenges and high attrition during the devel-
opmentphase,andtheacceptancethatmanyreasonsforfailurearedirectlyattributabletothe
chemical structure of the drug candidate, medicinal chemists have a duty to design the best
molecule possible to advance from research into development and beyond.
The aim of this book, through a series of monographs by leading scientists from across the
world, from major pharmaceutical companies, biotechnology companies, contract research
organisations and academia is to prepare the medicinal chemist to spot the good chances.
The book covers the whole R&D process from target validation through to late stage clinical
trials, through descriptions of the background science, the process, learnings, case studies,
leading references and even hints and tips.
The foreword has been written by one of our industry’s most respected scientists, Simon
Campbell CBE FRS, FMedSci. Simon Campbell joined Pfizer as a Medicinal Chemist in 1972,
andwasakeymemberoftheteamsthatledtosuchblockbusterdrugsasCardura,Norvascand
Viagra.HewentontobecomePfizer’sSeniorVicePresidentforWorld-wideDrugDiscoveryand
MedicinalR&DinEurope.HewasPresidentoftheRoyalSocietyofChemistryfrom2004to2006
TheHandbookofMedicinalChemistry:PrinciplesandPractice
EditedbyAndrewDavisandSimonEWard
rTheRoyalSocietyofChemistry2015
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
v
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vi Preface
and maintains a very active and influential role in our industry. With his considerable experi-
ence Simon provides us with his personal learnings, and the undoubted opportunities for
medicinal chemistry looking forward.
The early chapters describe the tools of the medicinal chemist’s trade such as physical or-
ganic chemistry, computational chemistry and QSAR, library design, fragment based lead
5 generation and structure based design.
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P0 The middle section of the book covers the supporting scientific disciplines, including assay
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6- development, receptor pharmacology and in vivo model development, drug metabolism and
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18 pharmacokinetics, molecular biology, toxicology and translational science, computational
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26 biology and of critical importance, intellectual property.
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17 The later sections of the book describe the overall research and development process from
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97 target generation, lead identification and optimisation through to pharmaceutical develop-
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3 ment, clinical development and chemical development, including the importance of efficient
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0. project management.
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oi: Due to the high levels of failure faced during drug development, case studies of successful
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g | R&D are hard to find, but are invaluable as a touchstone for pathways to success. So the last
c.or three chapters provide case studies of drugs that made it into the later stages of clinical de-
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s.r velopment and/or onto the market, Brilinta, Aleglitazar and Lapatinib. Even during the prep-
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pu arationofthisbook,oneofourcasestudieswasunfortunatelyhaltedduringPhaseIIItrials.As
p:// sadasPhaseIIIfailureis,fewdrugsreachthisstageofclinicaldevelopmentandtherearemany
n htt lessons to be learnt in this story that justify its esteemed place in this section.
4 o The book began as life as a proposal to update to a 3rd edition the Royal Society of
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20 Chemistry’s long running publication ‘‘Principles and Practice of Medicinal Chemistry’’.
ber The first edition was published over 20 years ago, and was a spin-out from the biannual
35:56. Decem rRuonynalinSgofcoiertoyvoefr4C0hyeemairsstaryndMheadsicbineeanl CthheetmraisintriyngSugmromunedr fWoromrkasnhyopo,fwouhricihndiutssetlrfy’hsalesabdeineng
08:09 medicinal chemists. The 3rd edition proposal retained some distinctive features of its pre-
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d o decessors, being highly practitioner focused, but grew to incorporate a broader context and
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sh to reflect the changing reader demographic reflected in the changing industry and drug
ubli discovery environments. It also grew to incorporate new opportunities that did not exist
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20 years ago.
Paperpublishingisasvalidtodayasithaseverbeen,butmobilecomputingande-publishing
arechangingthewayinformationcanbeusedandpresented.E-publicationsallow interaction
with the content which cannot occur with paper. App-stores allow easy access to sophisticated
softwarethatcanbedeliveredandupdatedwithease.Manytoolspotentiallyusefultomedicinal
chemistsdonotexistinaneasilyaccessibleandsecuremanner.Soforthe3rdeditionwewanted
to develop, as a companion to the print book, a set of useful medicinal chemistry apps to run
locallyontabletcomputers,andalsoafullyinteractivee-bookversiontocomplementthepaper
copy. The apps would bring to life concepts described within the book chapters and allow
chemists to quickly and easily find help in their design challenges.
While even 10 years ago protein structure visualisation and small molecule modelling re-
quired high-end workstations and costly software, nowadays this can be accomplished on a
tablet computer. Indeed, the frontispiece image of this book was designed inside the freeware
appiMolviewfromMolsoftonanAppleiPad3.SimilarlystaticpicturesofX-raycrystalstructures
withinthechapterscanbebroughtintohighresolutionreality,andthereadercaninteractwith
the exact data that the original medicinal chemist used in the documented design. Structures
canlinktoChemSpiderorevenWikipediaandotheronlineresourcesprovidingdeepercontext,
and hyperlinks to regulatory guidance mean the medicinal chemist has access to primary in-
formation sources relevant to each chapter.
View Online
Preface vii
So while this 3rd edition was inspired by its predecessors, with the companion apps and the
e-book format, it was time to change the book’s name. We hoped the book would become an
everyday companion for the practicing medicinal chemist, and so the title ‘‘Handbook of
Medicinal Chemistry’’ seemed appropriate. With both print and electronic format and
companionappswehopethat,withthishandbook,wecanmorefullypreparethemindofthe
5 medicinal chemist to pick the right chances.
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3 Contents
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3 Introduction xxiii
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doi: Chapter 1 Physicochemical Properties and Compound Quality 1
g | M. Paul Gleeson, Paul D. Leeson and Han van de Waterbeemd
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bs.r 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
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n 1.2.2 Calculating log P and log D . . . . . . . . . . . . . . . . . . . . . . . . . 5
o 7.4
14 1.2.3 Ionisation Constants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
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er 2 1.2.4 Hydrogen Bonding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
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8:9 1.2.7 Calculating Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
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n 1.2.8 Other Compound Quality Indicators . . . . . . . . . . . . . . . . . . . . 8
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ed 1.3 Compound Quality and Drug-likeness . . . . . . . . . . . . . . . . . . . . . . . . 8
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blis 1.3.1 The Rule of Five, and Other Physical Properties. . . . . . . . . . . . 9
Pu 1.3.2 ADME and Physicochemical Properties . . . . . . . . . . . . . . . . . . 9
1.3.3 Toxicity and Physicochemical Properties . . . . . . . . . . . . . . . . . 11
1.3.4 Effect of Time on Oral Drug Properties . . . . . . . . . . . . . . . . . . 12
1.3.5 Non-Oral Drug Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.3.6 Effect of Target Class . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.3.7 Effect of the Individual Chemist and the Organisation. . . . . . . 16
1.3.8 ‘Exception’ Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.4 The Drug Discovery Process: Does It Unknowingly Introduce
A Bias In Molecular Properties?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.4.1 Ligand Efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.4.2 Multi-Objective Parameter Optimisation . . . . . . . . . . . . . . . . . 20
1.5 Hints and Tips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1.6 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
TheHandbookofMedicinalChemistry:PrinciplesandPractice
EditedbyAndrewDavisandSimonEWard
rTheRoyalSocietyofChemistry2015
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
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x Contents
Chapter 2 Parallel Synthesis and Library Design 32
Andy Merritt
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.2 The Start of Combichem in Drug Discovery . . . . . . . . . . . . . . . . . . . 33
9 2.3 From Peptides to Small Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . 37
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1 it’s All About Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
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2 2.6 Realising a Collection—Technology Development and Commercial
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1 Offerings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
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9 2.7 Design Strategies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
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03 2.8 Diversity Collections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
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0. 2.9 Targeted Libraries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
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oi: 2.10 Combinatorial Power in Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
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g | 2.11 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
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c. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
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p:// Chapter 3 Useful Computational Chemistry Tools for Medicinal Chemistry 66
htt Darren V. S. Green
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1 3.1 Physics Based vs. Empirical Models . . . . . . . . . . . . . . . . . . . . . . . . . . 66
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8:9 3.2.3 Electronic Distribution and Electrostatic Isopotentials. . . . . . . 73
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on 3.2.4 Dimensional Molecular Similarity . . . . . . . . . . . . . . . . . . . . . . 74
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e 3.2.5 Energy Minimisation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
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P 3.4 Modelling Solvation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.5 Conformations, Conformational Energy and Drug Design. . . . . . . . . . 80
3.6 Quantifying Molecular Interactions from Experimental Data. . . . . . . . 84
3.7 Docking and Scoring Functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
3.8 Examples of Impactful Computational Chemistry on Drug Design . . . 87
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Chapter 4 Structure-Based Design for Medicinal Chemists 96
Jeff Blaney and Andrew M. Davis
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
4.2 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
4.3 Interpreting X-ray Crystal Structures. . . . . . . . . . . . . . . . . . . . . . . . . 99
4.4 Visualizing Shape Complementarity . . . . . . . . . . . . . . . . . . . . . . . . . 99
4.5 What Drives Binding? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
4.6 Enthalpy–Entropy Compensation . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
4.7 Small Molecules Bind in Their Lowest Energy, Preferred
Conformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4.8 Preferred Protein–Ligand Interactions . . . . . . . . . . . . . . . . . . . . . . . 104
4.9 Hydrogen Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107