Brow

n(Ed.)

Edited by Nathan Brown

54 Methods and Principles in Medicinal Chemistry

Bioisosteresin Medicinal Chemistry

Bioisosteres

inM

edicinal Chem

istry

Volume 54

Series Editors:R. Mannhold,H. Kubinyi,G. Folkers

www.wiley-vch.de

Written with the practicing medicinal chemist in mind, this is the firstmodern handbook to systematically address the topic of bioisosterism.As such, it provides a ready reference on the principles and methods ofbioisosteric replacement as a key tool in preclinical drug development.

The first part provides an overview of bioisosterism, classicalbioisosteres and typical molecular interactions that need to be consid-ered, while the second part describes a number of molecular databases assources of bioisosteric identification and rationalization. The third partcovers the four key methodologies for bioisostere identification and re-placement: physicochemical properties, topology, shape, and overlays ofprotein-ligand crystal structures. In the final part, several real-world exam-ples of bioisosterism in drug discovery projects are discussed.

With its detailed descriptions of databases, methods and real-life casestudies, this is tailor-made for busy industrial researchers with little timefor reading, while remaining easily accessible to novice drug developersdue to its systematic structure and introductory section.

Nathan Brown is the Head of the In Silico Medicinal Chemistrygroup in the Cancer Research UK Cancer Therapeutics Unit atthe Institute of Cancer Research in London (UK). At the ICR,Dr. Brown and his group support the entire drug discovery port-folio together with developing new computational methodologiesto enhance the drug design work.

Nathan Brown conducted his doctoral research in Sheffieldwith Professor Peter Willett focusing on evolutionary algorithmsand graph theory applied to challenges in chemoinformatics. Aftera two-year Marie Curie fellowship in Amsterdam in collaborationwith Professor Johann Gasteiger in Erlangen, he joined theNovartis Institutes for BioMedical Research in Basel for a three-year Presidential fellowship in Basel working with Professors PeterWillett and Karl-Heinz Altmann.

His work has led to the pioneering work on mulitobjectivedesign in addition to a variety of discoveries and method

development in bioisosteric identification and replacement,scaffold hopping, molecular descriptors and statistical modeling.Nathan continues to pursue his research in all aspects ofmedicinal chemistry.

denovo

in silico

57268File AttachmentCover.jpg

Edited by

Nathan Brown

Bioisosteres in Medicinal

Chemistry

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

Previous Volumes of this Series:

Gohlke, Holger (Ed.)

Protein-Ligand Interactions2012

ISBN: 978-3-527-32966-3

Vol. 53

Kappe, C. Oliver / Stadler, Alexander / Dallinger, Doris

Microwaves in Organicand Medicinal ChemistrySecond, Completely Revised

and Enlarged Edition

2012

ISBN: 978-3-527-33185-7

Vol. 52

Smith, Dennis A. / Allerton, Charlotte /

Kalgutkar, Amit S. / van de Waterbeemd,

Han / Walker, Don K.

Pharmacokinetics and Metabolismin Drug Design

Third, Revised and Updated Edition

2012

ISBN: 978-3-527-32954-0

Vol. 51

De Clercq, Erik (Ed.)

Antiviral Drug Strategies

2011

ISBN: 978-3-527-32696-9

Vol. 50

Klebl, Bert / Müller, Gerhard / Hamacher,

Michael (Eds.)

Protein Kinases as Drug Targets2011

ISBN: 978-3-527-31790-5

Vol. 49

Sotriffer, Christoph (Ed.)

Virtual Screening

Principles, Challenges, and Practical

Guidelines

2011

ISBN: 978-3-527-32636-5

Vol. 48

Rautio, Jarkko (Ed.)

Prodrugs and Targeted DeliveryTowards Better ADME Properties

2011

ISBN: 978-3-527-32603-7

Vol. 47

Smit, Martine J. / Lira, Sergio A. /

Leurs, Rob (Eds.)

Chemokine Receptors as Drug Targets

2011

ISBN: 978-3-527-32118-6

Vol. 46

Ghosh, Arun K. (Ed.)

Aspartic Acid Proteases asTherapeutic Targets

2010

ISBN: 978-3-527-31811-7

Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)

Transporters as Drug Carriers

Structure, Function, Substrates

2009

ISBN: 978-3-527-31661-8

Vol. 44

Edited by Nathan Brown

Bioisosteres in Medicinal Chemistry

Series Editors

Prof. Dr. Raimund MannholdMolecular Drug Research GroupHeinrich-Heine-UniversitätUniversitätsstrasse 140225 DüsseldorfGermanymannhold@uni-duesseldorf.de

Prof. Dr. Hugo KubinyiDonnersbergstrasse 967256 Weisenheim am SandGermanykubinyi@t-online.de

Prof. Dr. Gerd FolkersCollegium HelveticumSTW/ETH Zurich8092 ZurichSwitzerlandfolkers@collegium.ethz.ch

Volume Editor

Dr. Nathan BrownThe Institute of Cancer ResearchCancer Research UK CancerTherapeutics Unit15 Cotswold RoadSutton SM2 5NGUnited Kingdom

All books published by Wiley-VCH are carefullyproduced. Nevertheless, authors, editors, and pub-lisher do not warrant the information contained inthese books, including this book, to be free of errors.Readers are advised to keep in mind that statements,data, illustrations, procedural details or other itemsmay inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication DataA catalogue record for this book is available from theBritish Library.

Bibliographic information published bythe Deutsche NationalbibliothekThe Deutsche Nationalbibliothek lists this publica-tion in the Deutsche Nationalbibliografie; detailedbibliographic data are available on the Internet athtt p://dnb.d-nb .de.

# 2012 Wiley-VCH Verlag & Co. KGaA,Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translationinto other languages). No part of this book may bereproduced in any form – by photoprinting, micro-film, or any other means – nor transmitted or trans-lated into a machine language without writtenpermission from the publishers. Registered names,trademarks, etc. used in this book, even when notspecifically marked as such, are not to be consideredunprotected by law.

Composition Thomson Digital, Noida, IndiaPrinting and Binding Markono Print Media Pte Ltd,SingaporeCover Design Schulz Grafik-Design, Fußgönheim

Print ISBN: 978-3-527-33015-7ePDF ISBN: 978-3-527-65433-8ePub ISBN: 978-3-527-65432-1mobi ISBN: 978-3-527-65431-4oBook ISBN: 978-3-527-65430-7

Printed in SingaporePrinted on acid-free paper

Contents

List of Contributors XIPreface XVA Personal Foreword XVII

Part One Principles 1

1 Bioisosterism in Medicinal Chemistry 3Nathan Brown

1.1 Introduction 31.2 Isosterism 31.3 Bioisosterism 61.4 Bioisosterism in Lead Optimization 91.4.1 Common Replacements in Medicinal Chemistry 91.4.2 Structure-Based Drug Design 91.4.3 Multiobjective Optimization 121.5 Conclusions 13

References 14

2 Classical Bioisosteres 15Caterina Barillari and Nathan Brown

2.1 Introduction 152.2 Historical Background 152.3 Classical Bioisosteres 172.3.1 Monovalent Atoms and Groups 172.3.2 Bivalent Atoms and Groups 172.3.3 Trivalent Atoms and Groups 182.3.4 Tetravalent Atoms 192.3.5 Ring Equivalents 192.4 Nonclassical Bioisosteres 202.4.1 Carbonyl Group 202.4.2 Carboxylic Acid 212.4.3 Hydroxyl Group 222.4.4 Catechol 22

V

2.4.5 Halogens 232.4.6 Amide and Esters 242.4.7 Thiourea 252.4.8 Pyridine 262.4.9 Cyclic Versus Noncyclic Systems 272.5 Summary 27

References 27

3 Consequences of Bioisosteric Replacement 31Dennis A. Smith and David S. Millan

3.1 Introduction 313.2 Bioisosteric Groupings to Improve Permeability 323.3 Bioisosteric Groupings to Lower Intrinsic Clearance 403.4 Bioisosteric Groupings to Improve Target Potency 433.5 Conclusions and Future Perspectives 47

References 49

Part Two Data 53

4 BIOSTER: A Database of Bioisosteres and Bioanalogues 55István Ujváry and Julian Hayward

4.1 Introduction 554.2 Historical Overview and the Development of BIOSTER 564.2.1 Representation of Chemical Transformations for Reaction

Databases 564.2.2 The Concept of ‘‘Biosteric Transformation’’ 574.2.3 Other Analogue and Bioisostere Databases 584.3 Description of BIOSTER Database 594.3.1 Coverage and Selection Criteria 594.3.2 Sources 594.3.3 Description of the Layout of Database Records 604.3.3.1 ID Code 604.3.3.2 Biosteric Transformation 604.3.3.3 Citation(s) 624.3.3.4 Activity 634.3.3.5 Fragments 634.3.3.6 Component Molecules and Fragments 644.4 Examples 644.4.1 Benzodioxole Bioisosteres 654.4.2 Phenol Bioisosteres 664.4.3 Ketoamides 664.5 Applications 694.6 Summary 704.7 Appendix 70

References 71

VI Contents

5 Mining the Cambridge Structural Database for Bioisosteres 75Colin R. Groom, Tjelvar S. G. Olsson, John W. Liebeschuetz,David A. Bardwell, Ian J. Bruno, and Frank H. Allen

5.1 Introduction 755.2 The Cambridge Structural Database 765.3 The Cambridge Structural Database System 785.3.1 ConQuest 785.3.2 Mercury 785.3.3 WebCSD 795.3.4 Knowledge-Based Libraries Derived from the CSD 805.4 The Relevance of the CSD to Drug Discovery 835.5 Assessing Bioisosteres: Conformational Aspects 845.6 Assessing Bioisosteres: Nonbonded Interactions 865.7 Finding Bioisosteres in the CSD: Scaffold Hopping and

Fragment Linking 915.7.1 Scaffold Hopping 915.7.2 Fragment Linking 925.8 A Case Study: Bioisosterism of 1H-Tetrazole and Carboxylic

Acid Groups 945.8.1 Conformational Mimicry 945.8.2 Intermolecular Interactions 945.9 Conclusions 97

References 98

6 Mining for Context-Sensitive Bioisosteric Replacementsin Large Chemical Databases 103George Papadatos, Michael J. Bodkin, Valerie J. Gillet,and Peter Willett

6.1 Introduction 1036.2 Definitions 1046.3 Background 1056.4 Materials and Methods 1096.4.1 Human Microsomal Metabolic Stability 1096.4.2 Data Preprocessing 1096.4.3 Generation of Matched Molecular Pairs 1106.4.4 Context Descriptors 1116.4.4.1 Whole Molecule Descriptors 1116.4.4.2 Local Environment Descriptors 1126.4.5 Binning of DP Values 1126.4.6 Charts and Statistics 1126.5 Results and Discussion 1136.5.1 General Considerations 1236.6 Conclusions 124

References 125

Contents VII

Part Three Methods 129

7 Physicochemical Properties 131Peter Ertl

7.1 Introduction 1317.2 Methods to Identify Bioisosteric Analogues 1327.3 Descriptors to Characterize Properties of Substituents

and Spacers 1327.4 Classical Methods for Navigation in the Substituent

Space 1357.5 Tools to Identify Bioisosteric Groups Based on Similarity

in Their Properties 1367.6 Conclusions 138

References 138

8 Molecular Topology 141Nathan Brown

8.1 Introduction 1418.2 Controlled Fuzziness 1418.3 Graph Theory 1428.4 Data Mining 1448.4.1 Graph Matching 1448.4.2 Fragmentation Methods 1458.5 Topological Pharmacophores 1468.6 Reduced Graphs 1498.7 Summary 151

References 152

9 Molecular Shape 155Pedro J. Ballester and Nathan Brown

9.1 Methods 1569.1.1 Superposition-Based Shape Similarity Methods 1569.1.2 Superposition-Free Shape Similarity Methods 1589.1.3 Choosing a Shape Similarity Technique for a Particular

Project 1609.2 Applications 1619.3 Future Prospects 164

References 165

10 Protein Structure 167James E. J. Mills

10.1 Introduction 16710.2 Database of Ligand–Protein Complexes 16810.2.1 Extraction of Ligands 16810.2.2 Assessment of Ligand and Protein Criteria 169

VIII Contents

10.2.3 Cavity Generation 17010.2.4 Generation and Validation of SMILES String 17010.2.5 Generation of FASTA Sequence Files 17110.2.6 Identification of Intermolecular Interactions 17210.3 Generation of Ideas for Bioisosteres 17310.3.1 Substructure Search 17310.3.2 Sequence Search 17510.3.3 Binding Pocket Superposition 17510.3.4 Bioisostere Identification 17610.4 Context-Specific Bioisostere Generation 17710.5 Using Structure to Understand Common Bioisosteric

Replacements 17810.6 Conclusions 180

References 180

Part Four Applications 183

11 The Drug Guru Project 185Kent D. Stewart, Jason Shanley, Karam B. Alsayyed Ahmed,and J. Phillip Bowen

11.1 Introduction 18511.2 Implementation of Drug Guru 18711.3 Bioisosteres 18811.4 Application of Drug Guru 19411.5 Quantitative Assessment of Drug Guru Transformations 19511.6 Related Work 19711.7 Summary: The Abbott Experience with the Drug

Guru Project 197References 198

12 Bioisosteres of an NPY-Y5 Antagonist 199Nicholas P. Barton and Benjamin R. Bellenie

12.1 Introduction 19912.2 Background 19912.3 Potential Bioisostere Approaches 20112.4 Template Molecule Preparation 20412.5 Database Molecule Preparation 20612.6 Alignment and Scoring 20612.7 Results and Monomer Selection 20712.8 Synthesis and Screening 20812.9 Discussion 20912.10 SAR and Developability Optimization 21112.11 Summary and Conclusion 214

References 214

Contents IX

13 Perspectives from Medicinal Chemistry 217Nicholas A. Meanwell, Marcus Gastreich, Matthias Rarey, Mike Devereux,Paul L.A. Popelier, Gisbert Schneider, and Peter Willett

13.1 Introduction 21713.2 Pragmatic Bioisostere Replacement in Medicinal Chemistry:

A Software Makers Viewpoint 21913.3 The Role of Quantum Chemistry in Bioisostere Prediction 22113.4 Learn from ‘‘Naturally Drug-Like’’ Compounds 22313.5 Bioisosterism at the University of Sheffield 224

References 227

Index 231

X Contents

List of Contributors

XI

Frank H. AllenCambridge Crystallographic DataCentre (CCDC)12 Union RoadCambridge CB2 1EZUK

Karam B. Alsayyed AhmedUniversity of North Carolina atGreensboroDepartment of Chemistry & BiochemistryCenter for Drug DesignGreensboro, NC 27410USA

Pedro J. BallesterEuropean Bioinformatics InstituteWellcome Trust Genome CampusHinxton, Cambridge CB10 1SDUK

David A. BardwellCambridge Crystallographic DataCentre (CCDC)12 Union RoadCambridge CB2 1EZUK

Caterina BarillariThe Institute of Cancer ResearchCancer Research UK CancerTherapeutics Unit15 Cotswold RoadSutton SM2 5NGUK

Nicholas P. BartonGlaxoSmithKline PharmaceuticalsNew Frontiers Science Park (North)Coldharbour RoadHarlow, Essex CM15 5ADUK

Michael J. BodkinEli Lilly LimitedErl Wood ManorWindlesham, Surrey GU20 6PHUK

J. Phillip BowenUniversity of North Carolina atGreensboroDepartment of Chemistry &BiochemistryCenter for Drug DesignGreensboro, NC 27410USA

and

Mercer UniversityCollege of Pharmacy and HealthSciencesDepartment of Pharmaceutical Sciences3001 Mercer University DriveAtlanta, GA 30341USA

Nathan BrownThe Institute of Cancer ResearchCancer Research UK CancerTherapeutics Unit15 Cotswold RoadSutton SM2 5NGUK

Ian J. BrunoCambridge Crystallographic DataCentre (CCDC)12 Union RoadCambridge CB2 1EZUK

Mike DevereuxUniversity of BaselKlingelbergstrasse 804056 BaselSwitzerland

Peter ErtlNovartis Institutes for BioMedicalResearchNovartis Campus4056 BaselSwitzerland

Marcus GastreichBioSolveITAn der Ziegelei 7953757 St. AugustinGermany

Valerie J. GilletThe University of SheffieldInformation SchoolRegent Court211 PortobelloSheffield S1 4DPUK

Colin R. GroomCambridge Crystallographic DataCentre (CCDC)12 Union RoadCambridge CB2 1EZUK

Julian HaywardDigital Chemistry Ltd30 Kiveton LaneTodwick, Sheffield S26 1HLUK

John W. LiebeschuetzCambridge Crystallographic DataCentre (CCDC)12 Union RoadCambridge CB2 1EZUK

Nicholas A. MeanwellBristol-Myers Squibb PharmaceuticalResearch and DevelopmentDepartment of Medicinal Chemistry5 Research ParkwayWallingford, CT 06492USA

David MillanSandwich LaboratoriesPfizer Global Research andDevelopmentRamsgate RoadSandwich, Kent CT13 9NJUK

James E. J. MillsSandwich LaboratoriesPfizer Global Research andDevelopmentRamsgate RoadSandwich, Kent CT13 9NJUK

XII List of Contributors

Tjelvar J. OlssonCambridge Crystallographic DataCentre (CCDC)12 Union RoadCambridge CB2 1EZUK

George PapadatosEli Lilly LimitedErl Wood ManorWindlesham, Surrey GU20 6PHUK

Paul L.A. PopelierUniversity of ManchesterManchester Interdisciplinary Biocentre(MIB)131 Princess StreetManchester M1 7DNUK

and

University of ManchesterSchool of ChemistryOxford RoadManchester M13 9PLUK

Matthias RareyZBH University of HamburgBundesstrasse 4320146 HamburgGermany

Gisbert SchneiderETH ZurichInstitute of Pharmaceutical Sciences8093 ZurichSwitzerland

Jason ShanleyAbbott LaboratoriesGlobal Pharmaceutical Research andDevelopmentDepartment of Structural Biology100 Abbott Park RoadAbbott Park, IL 60031USA

Dennis A. SmithSandwich LaboratoriesPfizer Global Research andDevelopmentRamsgate RoadSandwich, Kent CT13 9NJUK

Kent D. StewartAbbott LaboratoriesGlobal Pharmaceutical Research andDevelopmentDepartment of Structural Biology100 Abbott Park RoadAbbott Park, IL 60031USA

István UjváryiKem BTBúza u. 321033 BudapestHungary

Peter WillettUniversity of SheffieldInformation SchoolSheffield S1 4DPUK

List of Contributors XIII

Preface

Bioisosteric replacement of substituents, ring atoms, linkers, and other groups aimsto generate chemical substitutes with related biological properties, in the hope thatthe new analogues may have somewhat better properties. Such replacements are thetoolbox of medicinal chemists to optimize their lead structures with respect tolipophilicity, solubility, activity, selectivity, absorption, metabolism, and lack of toxicand other side effects. Whenever an analogue with some improved properties isobserved, the new compound is taken as the starting point for further modification.In this evolutionary procedure, either a preclinical or a clinical candidate results orthe project has to be terminated, without success. Whereas the whole process quiteoften follows a trial and error procedure, certain empirical rules developed inmedicinal chemistry. Very simple ones are, for example, the replacement of ahydrogen atom in the para-position of a benzene ring, to avoid rapid metabolicdegradation, or, on the other hand, the introduction of an aromatic methyl groupinstead of a chlorine atom, to avoid too long biological half-life. More sophisticatedrules exist for modification of the ligands of certain targets, for example, proteases orkinases.

The organization of this book follows a logical sequence, starting with Part One onthe principles of bioisosterism, including an introductory chapter, and chapters onclassical bioisosteres in medicinal chemistry and the logical but often surprisingconsequences of bioisosteric replacement. Part Two presents a database on bioisos-teres and bioanalogues and discusses the search for bioisosteres, using the Cam-bridge Structure Database of 3D structures of small molecules, as well as theminingof bioisosteric pairs. Part Three presents methods to identify bioisosteres under theaspect of physicochemical properties, molecular topology, molecular shape, andprotein 3D structures. Part Four describes a computer program for drug design,using medicinal chemistry rules, discusses the bioisosteric modification of a recep-tor antagonist, and ends with a concluding chapter on perspectives from medicinalchemistry.

Whereas some reviews on bioisosteres are found in the literature, as well aschapters inmedicinal chemistry books, no dedicatedmonograph on bioisosteres hasbeen published so far. Thus, we are very grateful to Nathan Brown for editing such abook, which will help novices in the field as well as experienced scientists to managelead structure optimization in an even more rational manner. In addition, we are

XV

very much indebted to FrankWeinreich andHeike Nöthe, both at Wiley-VCH. Theirsupport and ongoing engagement, not only for this book but also for the whole series‘‘Methods and Principles in Medicinal Chemistry,’’ adds to the success of thisexcellent collection of monographs on various topics, all related to drug research.

March 2012 Raimund MannholdDüsseldorf Hugo KubinyiWeisenheim am Sand Gerd FolkersZürich

XVI Preface

A Personal Foreword

‘‘Hamlet: Do you see yonder cloud thats almost in shape of a camel?Polonius: By th Mass, and tis like a camel, indeed.Hamlet: Methinks it is like a weasel.Polonius: It is backed like a weasel.Hamlet: Or like a whale.Polonius: Very like a whale.’’

Hamlet, Act III, Scene IIWilliam Shakespeare

The essence of design is the identification of appropriate constituents and theircareful arrangement in sympathy with the requirements of the desired object. Thesame principles apply in drug design, where the components are elements andelemental groups, and their arrangement is achieved through the synthetic organicchemistry that is undertaken. The ultimate requirement in the design of new drugsis an entity that summons a physiological response of benefit to the patient.

In this book, we cover the key aspects of drug design through the identificationand replacement of bioisosteric groups within the context of the drug design ethic.Bioisosterism is a phenomenon where molecular groups are functionally similar,that is, they have a similar biological effect, while modulating other properties.This is the first book to provide a general overview of the field of bioisosterism at atime when its application has become a formal process. There are now manyinformation sources and design tools available to assist the medicinal chemist inthe identification of relevant bioisosteres.

The first part of this book covers the historical aspects of bioisosterism, from itsfounding principles of isosterism from Langmuir through defined sets of classicalisosteres and bioisosteres, to the potential consequences of bioisosteric replacementin context.

A considerable amount of knowledge has been collated in recent years, in largemolecular databases with metadata that can be analyzed and brought to bear inbioisosteric replacement. Knowledge-based methods form the second part, coveringexperimentally determined bioisosteric replacements from the medicinal chemistry

XVII

literature; small-molecule crystal identification of bioisosteres; and miningunknown bioisosteres from these databases through the application of recentlydeveloped methods for their identification.

One can describe a molecule in many ways and the same applies to bioisosteres.Molecular descriptor methods are covered in the third part by the application ofdifferent representations. A number of computational approaches to bioisostericreplacement are covered in chapters on physicochemical properties, moleculartopology, molecular shape, and the use of protein structure information. Eachchapter covers many common methods and overviews of when best to apply thesemethods, and where they have been successfully applied.

This book concludes with two case studies of where bioisosteric replacementstrategies have been applied in drug discovery, to provide demonstrable evidence oftheir utility. Finally, a few leading scientists in this field have kindly providedpersonal perspectives on bioisosterism and its relevance to drug discovery.

My sincere wish is that you enjoy reading this book as much as I did workingwith the very talented team of scientists who contributed chapters. I would also liketo thank the publishing team and the series editors for their help in bringing thisbook together.

London, 2012 Nathan Brown

XVIII A Personal Foreword

Part onePrinciples

Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown� 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

j1

1Bioisosterism in Medicinal ChemistryNathan Brown

1.1Introduction

One of the key challenges for the medicinal chemist today is the modulation andmediation of the potency of a small-molecule therapeutic against its biological target.In addition, it is essential to ensure that the molecule reaches its target effectivelywhile also ensuring that it satisfies necessary safety requirements. One of the mostsignificant approaches to assist in efficiently navigating the available chemistry spaceis that of bioisosteric replacement.

This book, the first dedicated solely to the subject of bioisosterism, covers the fieldfrom the very beginning to its development as a reliable and well-used approach toassist in drug design. This book is split into four parts. The first part covers theprinciples and theory behind isosterism and bioisosterism. The second part inves-tigates methods that apply knowledge bases of experimental data from a variety ofsources to assist in decision making. The third part reports on the four main com-putational approaches to bioisosteric identification and replacement usingmolecularproperties, topology, shape, and protein structure. This book concludes with real-world examples of bioisosterism in application and a collection of reflections andperspectives on bioisosteric identification and replacement frommany of the currentleaders in the field.

This chapter provides an overview of the history of bioisosterism from its beginn-ing in the early twentieth century to the present day. We also provide an overview ofthe importance of judicious bioisosteric replacement in lead optimization to assist inthe path toward a viable clinical candidate and, ultimately, a drug.

1.2Isosterism

James Moir [1] first considered isosterism in all but name, in 1909. It was not until1919 that the term isosterism was given to this phenomenon by Irving Langmuir [2]in his landmark paper Isomorphism, isosterism and covalence. The focus of this

j3

Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown� 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.

early isosterism work was on the electronic configuration of atoms. Langmuir usedexperiment to identify the correspondence between the physical properties of dif-ferent substances. Langmuir, in accordancewith the octet rulewhere atomswill oftencombine to have eight electrons in their valence shells, compared the number andarrangement of electrons between nitrogen, carbonmonoxide, and the cyanogen ionand identified that these would be the same. This relationship was demonstrated tobe true between nitrogen and carbonmonoxide in terms of their physical properties.The same similarities were also reported between nitrous oxide and carbon dioxidewhen taking experimental data from Landolt–B€ornsteins tables and Abeggs hand-book (Table 1.1).

However, Langmuir identified one distinct property that is substantially differentbetween nitrous oxide and carbon dioxide, the freezing point: �102 and �56 �C,respectively. Evidence for this was assumed to be due to the freezing point beingabnormally sensitive to even slight differences in structure.

With this observation of the correlation between the structure and arrangement ofelectrons with physical properties, Langmuir defined the neologism calling themisosteres, or isosteric compounds. Langmuir defined isosterism as follows:

Comolecules are thus isosteric if they contain the same number and arrange-ment of electrons. The comolecules of isosteres must, therefore, contain thesame number of atoms. The essential differences between isosteres are con-fined to the charges on the nuclei of the constituent atoms. Thus in carbondioxide the charges on the nuclei of the carbon and oxygen atoms are 6 and 8,respectively, and there are 2� 8þ 6¼ 22 electrons in the molecule. In nitrousoxide the number of charges on the nitrogen nuclei is 7, but the total numberof electrons in themolecule is again 2� 7þ 8¼ 22. The remarkable similarityof the physical properties of these two substances proves that their electronsare arranged in the same manner.

Table 1.1 Experimental data from Landolt–B€ornsteins tables and Abeggs handbook for nitrousoxide (N2O) and carbon dioxide (CO2).

Property N2O CO2

Critical pressure (atm) 75 77Critical temperature (�C) 35.4 31.9Viscosity at 20 �C 148� 10�6 148� 10�6Heat conductivity at 100 �C 0.0506 0.0506Density of liquid at �20 �C 0.996 1.031Density of liquid at þ 10 �C 0.856 0.858Refractive index of liquid, D line, 16 �C 1.193 1.190Dielectric constant of liquid at 0 �C 1.598 1.582Magnetic susceptibility of gas at 40 atm, 16 �C 0.12� 10�6 0.12� 10�6Solubility in water at 0 �C 1.305 1.780Solubility in alcohol at 15 �C 3.25 3.13

4j 1 Bioisosterism in Medicinal Chemistry

The list of isosteres that Langmuir described in 1919 is given in Table 1.2.Langmuir extended his concept of isosterism to predicting likely crystal formsusing sodium and fluorine ions as exemplars, these having been solved byWilliam Henry Bragg and William Lawrence Bragg – father and son who weretogether awarded the Nobel Prize for Physics in 1915. Since the magnesiumand oxygen ions are isosteric with the sodium and fluorine ions, it follows thatmagnesium oxide will have a crystal structure that is identical to that of sodiumfluoride.

In 1925, H.G. Grimm [3] extended the concept of isosterism, introduced byLangmuir, with Grimms hydride displacement law:

Atoms anywhere up to four places in the periodic system before an inert gaschange their properties by uniting with one to four hydrogen atoms, in sucha manner that the resulting combinations behave like pseudoatoms, whichare similar to elements in the groups one to four places, respectively, totheir right.

Therefore, according to this law, the addition of hydrogen to an atom will result ina pseudoatom with similar properties to the atom of the next highest atomic number.So, CH is isosteric with N and NH is isosteric with O and so on.

Table 1.2 List of isosteres defined by Langmuir in 1919.

Type Isosteres

1 H�, He, Liþ

2 O2�, F�, Ne, Naþ, Mg2þ, Al3þ

3 S2�, Cl�, A, Kþ, Ca2þ

4 Cuþ, Zn2þ

5 Br�, Kr, Rbþ, Sr2þ

6 Agþ, Cd2þ

7 I�, Xe, Csþ, Ba2þ

8 N2, CO, CN�

9 CH4, NH4þ

10 CO2, N2O, N3�, CNO�

11 NO3�, CO3

2�

12 NO2�, O3

13 HF, OH�

14 ClO4�, SO4

2�, PO43�

15 ClO3�, SO4

2�, PO43�

16 SO3, PO3�

17 S2O62�, P2O6

4�

18 S2O72�, P2O7

4�

19 SiH4, PH4þ

20 MnO4�, CrO4

2�

21 SeO42�, AsO4

3�

1.2 Isosterism j5

Beginning in 1932, FriedrichErlenmeyer [4, 5] extended the concepts fromGrimmfurther and the first applications of isosterism to biological systems. Erlenmeyerredefined isosteres as:

. . .elements, molecules or ions in which the peripheral layers of electronsmay be considered identical.

In addition, Erlenmeyer also proposed the following three additions to the conceptof isosteres:

1) All elements within the same group in the periodic table are isosteres of eachother. Therefore, silicon and carbon are isosteres of each other, as are oxygenand sulfur.

2) Pseudoatoms are included to characterize groups that appear superficiallydifferent but are actually very similar in physical properties. Pseudohalogensare an instance of this class, where Cl � CN � SCN, and so on.

3) Finally, ring equivalences are included to permit isosteric matches betweendifferent ring systems. One example is the isosteric properties between benzeneand thiophene, where �CH¼CH� � �S�.

It was with Erlenmeyer that the concept of bioisosterism was introduced todifferentiate from classical isosteres, ensuring its relevance to medicinal chemistry.The introduction of ring equivalences is significant. This was the formalization ofwhat we consider to be a bioisosteric comparison and is the first definition of mostrelevance to medicinal chemistry.

1.3Bioisosterism

Classical isosteres are traditionally categorized into the following distinctgroupings [6]:

1) Monovalent atoms or groups.2) Divalent atoms or groups.3) Trivalent atoms or groups.4) Tetrasubstituted atoms.5) Ring equivalents.

A number of classical bioisosteric examples are provided in Table 1.3 that illustratetypical replacements possible in each of these five groups.

However, more recent definitions of isosterism, and more specifically bioisoster-ism, relax these constraints and permit bioisosteric pairings betweenmoieties that donot necessarily contain the same number of atoms. Specifically, nonclassical bioi-sosteres include the addition of the following two groups:

1) Rings versus acyclic structures.2) Exchangeable groups.

6j 1 Bioisosterism in Medicinal Chemistry