Bioisosteres in medicinal chemistry

List of Contributors XI Preface XV A Personal Foreword XVII Part One Principles 1 1 Bioisosterism in Medicinal Chemistry 3 Nathan Brown 1.1 Introduction 3 1.2 Isosterism 3 1.3 Bioisoster

Bioisosteres in MedicinalChemistry

Methods and Principles in Medicinal Chemistry

Edited by R Mannhold, H Kubinyi, G Folkers

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

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Bioisosteres in Medicinal Chemistry

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List of Contributors XI

Preface XV

A Personal Foreword XVII

Part One Principles 1

1 Bioisosterism in Medicinal Chemistry 3

Nathan Brown

1.1 Introduction 3

1.2 Isosterism 3

1.3 Bioisosterism 6

1.4 Bioisosterism in Lead Optimization 9

1.4.1 Common Replacements in Medicinal Chemistry 9

1.4.2 Structure-Based Drug Design 9

2.3.1 Monovalent Atoms and Groups 17

2.3.2 Bivalent Atoms and Groups 17

2.3.3 Trivalent Atoms and Groups 18

3 Consequences of Bioisosteric Replacement 31

Dennis A Smith and David S Millan

3.1 Introduction 31

3.2 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 55

István Ujváry and Julian Hayward

4.1 Introduction 55

4.2 Historical Overview and the Development of BIOSTER 564.2.1 Representation of Chemical Transformations for Reaction

Databases 56

4.2.2 The Concept of‘‘Biosteric Transformation’’ 57

4.2.3 Other Analogue and Bioisostere Databases 58

4.3 Description of BIOSTERDatabase 59

4.3.1 Coverage and Selection Criteria 59

75Colin R Groom, Tjelvar S G Olsson, John W Liebeschuetz,

David A Bardwell, Ian J Bruno, and Frank H Allen

5.1 Introduction 75

5.2 The Cambridge Structural Database 76

5.3 The Cambridge Structural Database System 78

5.3.1 ConQuest 78

5.3.2 Mercury 78

5.3.4 Knowledge-Based Libraries Derived from the CSD 80

5.4 The Relevance of the CSD to Drug Discovery 83

5.5 Assessing Bioisosteres: Conformational Aspects 84

5.6 Assessing Bioisosteres: Nonbonded Interactions 86

5.7 Finding Bioisosteres in the CSD: Scaffold Hopping and

6 Mining for Context-Sensitive Bioisosteric Replacements

in Large Chemical Databases 103

George Papadatos, Michael J Bodkin, Valerie J Gillet,

and Peter Willett

6.1 Introduction 103

6.2 Definitions 104

6.4 Materials and Methods 109

6.4.1 Human Microsomal Metabolic Stability 109

6.4.2 Data Preprocessing 109

6.4.3 Generation of Matched Molecular Pairs 110

6.4.4 Context Descriptors 111

6.4.4.1 Whole Molecule Descriptors 111

6.4.4.2 Local Environment Descriptors 112

6.4.5 Binning ofDP Values 112

6.4.6 Charts and Statistics 112

6.5 Results and Discussion 113

6.5.1 General Considerations 123

6.6 Conclusions 124

References 125

Part Three Methods 129

17010.2.4 Generation and Validation of SMILES String 170

10.2.5 Generation of FASTA Sequence Files 171

10.2.6 Identification of Intermolecular Interactions 172

10.3 Generation of Ideas for Bioisosteres 173

10.3.1 Substructure Search 173

10.3.2 Sequence Search 175

10.3.3 Binding Pocket Superposition 175

10.3.4 Bioisostere Identification 176

10.4 Context-Specific Bioisostere Generation 177

10.5 Using Structure to Understand Common Bioisosteric

Replacements 178

10.6 Conclusions 180

References 180

Part Four Applications 183

11 The Drug Guru Project 185

Kent D Stewart, Jason Shanley, Karam B Alsayyed Ahmed,

and J Phillip Bowen

11.1 Introduction 185

11.2 Implementation of Drug Guru 187

11.3 Bioisosteres 188

11.4 Application of Drug Guru 194

11.5 Quantitative Assessment of Drug Guru Transformations 195

11.6 Related Work 197

11.7 Summary: The Abbott Experience with the Drug

Guru Project 197

References 198

12 Bioisosteres of an NPY-Y5 Antagonist 199

Nicholas P Barton and Benjamin R Bellenie

12.1 Introduction 199

12.2 Background 199

12.3 Potential Bioisostere Approaches 201

12.4 Template Molecule Preparation 204

12.5 Database Molecule Preparation 206

12.6 Alignment and Scoring 206

12.7 Results and Monomer Selection 207

12.8 Synthesis and Screening 208

12.9 Discussion 209

12.10 SAR and Developability Optimization 211

12.11 Summary and Conclusion 214

References 214

13 Perspectives from Medicinal Chemistry 217

Nicholas A Meanwell, Marcus Gastreich, Matthias Rarey, Mike Devereux,Paul L.A Popelier, Gisbert Schneider, and Peter Willett

13.1 Introduction 217

13.2 Pragmatic Bioisostere Replacement in Medicinal Chemistry:

A Software Maker’s Viewpoint 219

13.3 The Role of Quantum Chemistry in Bioisostere Prediction 22113.4 Learn from‘‘Naturally Drug-Like’’ Compounds 223

13.5 Bioisosterism at the University of Sheffield 224

References 227

Index 231

X Contents

Karam B Alsayyed Ahmed

University of North Carolina at

Greensboro

Department of Chemistry & Biochemistry

Center for Drug Design

Greensboro, NC 27410

USA

Pedro J Ballester

European Bioinformatics Institute

Wellcome Trust Genome Campus

The Institute of Cancer Research

Cancer Research UK Cancer

Harlow, Essex CM15 5ADUK

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

J Phillip BowenUniversity of North Carolina atGreensboro

Department of Chemistry &

BiochemistryCenter for Drug DesignGreensboro, NC 27410USA

andMercer UniversityCollege of Pharmacy and HealthSciences

Department of Pharmaceutical Sciences

3001 Mercer University DriveAtlanta, GA 30341

USA

Nathan Brown

The Institute of Cancer Research

Cancer Research UK Cancer

12 Union RoadCambridge CB2 1EZUK

Julian HaywardDigital Chemistry Ltd

30 Kiveton LaneTodwick, Sheffield S26 1HLUK

John W LiebeschuetzCambridge Crystallographic DataCentre (CCDC)

12 Union RoadCambridge CB2 1EZUK

Nicholas A MeanwellBristol-Myers Squibb PharmaceuticalResearch and Development

Department of Medicinal Chemistry

5 Research ParkwayWallingford, CT 06492USA

David MillanSandwich LaboratoriesPfizer Global Research andDevelopment

Ramsgate RoadSandwich, Kent CT13 9NJUK

James E J MillsSandwich LaboratoriesPfizer Global Research andDevelopment

Ramsgate RoadSandwich, Kent CT13 9NJUK

XII List of Contributors

Cambridge Crystallographic Data

Eli Lilly Limited

Erl Wood Manor

Windlesham, Surrey GU20 6PH

Department of Structural Biology

100 Abbott Park RoadAbbott Park, IL 60031USA

Dennis A SmithSandwich LaboratoriesPfizer Global Research andDevelopment

Ramsgate RoadSandwich, Kent CT13 9NJUK

Kent D StewartAbbott LaboratoriesGlobal Pharmaceutical Research andDevelopment

Department of Structural Biology

100 Abbott Park RoadAbbott Park, IL 60031USA

István UjváryiKem BTBúza u 32

1033 BudapestHungaryPeter WillettUniversity of SheffieldInformation SchoolSheffield S1 4DPUK

Bioisosteric replacement of substituents, ring atoms, linkers, and other groups aims

to 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 the mining

of 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 in medicinal chemistry books, no dedicated monograph on bioisosteres hasbeen published so far Thus, we are very grateful to Nathan Brown for editing such abook, which will help novices in thefield as well as experienced scientists to managelead structure optimization in an even more rational manner In addition, we are

XV

support 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

Zürich

A Personal Foreword

‘‘Hamlet: Do you see yonder cloud that’s 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 ShakespeareThe 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 drugs

is 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 thefirst 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

Thefirst 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 replacement

in 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 like

to thank the publishing team and the series editors for their help in bringing thisbook together

Part one

Principles

Bioisosteres in Medicinal Chemistry, First Edition Edited by Nathan Brown

Ó 2012 Wiley-VCH Verlag GmbH & Co KGaA Published 2012 by Wiley-VCH Verlag GmbH & Co KGaA.

j1

is that of bioisosteric replacement.

This book, thefirst 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 Thefirst 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 using molecularproperties, 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 from many of the currentleaders in thefield

This chapter provides an overview of the history of bioisosterism from its 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

beginn-1.2

Isosterism

James Moir [1]first considered isosterism in all but name, in 1909 It was not until

1919 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

Bioisosteres in Medicinal Chemistry, First Edition Edited by Nathan Brown

Ó 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 accordance with the octet rule where atoms will oftencombine to have eight electrons in their valence shells, compared the number andarrangement of electrons between nitrogen, carbon monoxide, and the cyanogen ionand identified that these would be the same This relationship was demonstrated to

be true between nitrogen and carbon monoxide in terms of their physical properties.The same similarities were also reported between nitrous oxide and carbon dioxidewhen taking experimental data from Landolt–B€ornstein’s tables and Abegg’s 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 56C,respectively Evidence for this was assumed to be due to the freezing point being

“abnormally 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 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 8 þ 6 ¼ 22 electrons in the molecule In nitrousoxide the number of charges on the nitrogen nuclei is 7, but the total number

arrange-of electrons in the molecule is again 2 7 þ 8 ¼ 22 The remarkable similarity

of the physical properties of these two substances proves that their electronsare arranged in the same manner.”

Table 1.1 Experimental data from Landolt–B€ornstein’s tables and Abegg’s handbook for nitrous oxide (N 2 O) and carbon dioxide (CO 2 ).

Magnetic susceptibility of gas at 40 atm, 16C 0.12  10 6 0.12  10 6

4j1 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 andfluorine 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 Grimm’s 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 such

a 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 in

a 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.

Beginning in 1932, Friedrich Erlenmeyer [4, 5] extended the concepts from Grimmfurther and thefirst 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 concept

of 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, whereCH¼CH  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 thefirst definition of mostrelevance to medicinal chemistry

1.3

Bioisosterism

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

bioisoster-1) Rings versus acyclic structures

2) Exchangeable groups

6j1 Bioisosterism in Medicinal Chemistry

The origins of classical isosterism focused largely on the electronic similarity ofgroups rather than their functional similarity As investigation into thefield pro-gressed, it became obvious that these very defined rules on isosterism, althoughpowerful, were restrictive in particular to medicinal chemistry The addition of thelatter two groups for nonclassical bioisosteres permitted the mimicking of spatialarrangements, electronic properties, or another physicochemical property that isimportant for biological activity.

In extending and broadening the purer rules of classical isosterism, two scientistsare credited with progressing thefield of bioisosterism: Friedman and Thornber

In 1951, Friedman [7] provided thefirst definition closest to what we call ism today:

bioisoster-“[bioisosteres are structural moieties] which fit the broadest definition ofisosteres and have the same type of biological activity.”

With this definition, the generalization of what constitutes bioisosterism wasformed However, this definition really only considers the macromolecular recog-nition of bioisosteres, which is of course highly important, but largely ignores thespecifics of the numerous other physicochemical properties that are optimized in amedicinal chemistry project Friedman’s definition was followed in 1979 with themuch less specific definition from Thornber [8] of bioisosteres and nonclassicalbioisosteres:

“Bioisosteres are groups or molecules which have chemical and physicalsimilarities producing broadly similar biological properties.”

Table 1.3 Some examples of classical bioisosteres – groups in each row are equivalent.

Atfirst reading, this definition looks somewhat similar to Friedman’s, but it is therelevant importance of chemical and physical similarities that differentiates this fromFriedman’s definition In addition to this definition, Thornber also defined eightparameters that could be considered in making an alteration to a structural moiety toelicit a bioisosteric pairing:

1) Size: molecular weight

2) Shape: bond angles and hybridization states

3) Electronic distribution: polarizability, inductive effects, charge, and dipoles.4) Lipid solubility

5) Water solubility

6) pKa

7) Chemical reactivity, including likelihood of metabolism

8) Hydrogen bonding capacity

Depending on the particular property that is modified by a bioisosteric ment, the result will typically fall into one or more of the following:

replace-1) Structural: Structural moieties often have a role in maintaining a preferredconformation and parameters such as size and bond angle play a key role inachieving this Typically, this is particularly relevant for moieties that areembedded deep within the overall chemical structure Scaffold hopping can

be seen as an example of this, where the relative geometries of the exit vectorshave a very low tolerance to modification

2) Receptor interactions: When the moiety that is being replaced interacts directlywith a receptor or enzyme, then the most relevant parameters will be size, shape,electronic properties, pKa, chemical reactivity, and hydrogen bonding.3) Pharmacokinetics: Quite often during and after optimization of the directbiological response, it will be important to also optimize the absorption,transport, and excretion properties of the molecule In these situations, themost important parameters to consider are lipophilicity, hydrophilicity, hydro-gen bonding, and pKa

4) Metabolism: A particular moiety may be involved in blocking or assisting withmetabolism Chemical reactivity is therefore an important property to optimize.Thornber gave the example of chloro and methyl groups on benzene beingpotentially interchangeable for some situations However, the toluene derivativecould be metabolized to a benzoic acid with the result being a short half-life orunexpected side effects

These four key generalized parameters, with specific properties governing theoptimization of each, provide what can be formalized as the changes that may bemade in lead optimization to provide guidance on the optimization of functionalgroups that are bioisosteric

In 1991, Alfred Burger [9] defined bioisosterism as:

“Compounds or groups that possess near-equal molecular shapes andvolumes, approximately the same distribution of electrons, and which exhibitsimilar physicochemical properties .”

8j1 Bioisosterism in Medicinal Chemistry

Burger’s definition succinctly defines bioisosteres including all of the tioned extensions defined by other scientists in the field The next section focuses

aforemen-on the specific improvements in lead optimizatiaforemen-on that can be gained by prudentapplication of the concepts of bioisosterism

1.4

Bioisosterism in Lead Optimization

One of the processes where bioisosteric replacement can have a substantial impact,particularly in the discovery of a novel small-molecule therapeutic, is in the leadoptimization stage of a drug discovery project Once a lead molecule has beenidentified, the medicinal chemist is faced with the considerable challenge of makingsmall, defined changes to an identified core structure (also chemotype or scaffold) bythe addition or substitution of functional groups to test specific hypotheses Whilethe challenge of scaffold hopping (the replacement of the functional or specific exitgeometries of a molecular scaffold) is important, this challenge will only be con-sidered as a subset of bioisosteric replacement in this book [14–18]

1.4.1

Common Replacements in Medicinal Chemistry

When considering a medicinal chemistry project where a lead molecule has beenidentified, and also chemical handles, to permit the synthesis of many analogues,the project team will identify substituents that are potential bioisosteric replace-ments using a number of different methods Many of these methods will bediscussed in Parts Two and Three of this book from the literature and in silicomodeling approaches, respectively Southall and Ajay [10] reported a number

of common medicinal chemistry bioisosteric replacements from kinase drugcandidates (Table 1.4) Sildenafil (Viagra)  Vardenafil (Levitra) [PDE5 Inhibitor:Pfizer  Bayer AG, SP, GSK] Ciprofloxacin (Proquin)  Levofloxacin (Tavanic)[Antibacterial: Bayer AG Sanofi-Aventis] Gefitinib (Iressa)  Erlotinib (Tarceva)[EGFR Inhibitor: AZ Roche/ISI]

1.4.2

Structure-Based Drug Design

It is becoming increasingly common that protein–ligand cocrystal structures areavailable to assist early on in a drug design project The inclusion of structuralinformation allows the design of molecules that take into account what may or maynot be tolerated in a particular position, according to the conformations of key proteinstructure residues This is in contrast to only using the information within the ligandsthat have already been synthesized and tested The latter can lead to the assumptionthat the bioisosteric replacement must have the same bulk properties as the originalgroup or, more frequently, lead to inefficiency in the design process through the

unnecessary synthesis of molecules that function only to probe functional grouptolerability at different positions on a molecule.

The application of protein structures to suggest bioisosteric replacements will becovered more fully in Chapter 10

1.4.3

Multiobjective Optimization

As has been discussed previously, lead optimization involves the separate, althoughsometimes simultaneous, optimization of multiple parameters When consideringreplacement of key functional groups around a common molecular scaffold, thechemical space of potential molecules that could be synthesized (assuming no issues

in terms of synthetic accessibility, stability, etc.) is the product of the number offeasible replacement groups at each substitution point on the molecular scaffold.For example, a project with one chemical scaffold that has three points of variation,using a conservative set of 50 possible monomers at each substitution point,generates a potential project chemical space (i.e., the set of all molecules that could

be synthesized) of 125 000 Typically, a medicinal chemistry project can only realizethe synthesis of a small proportion of these virtual compounds, for example,approximately 1% Therefore, the design of which molecules to synthesize and test

is of great importance to ensure that those molecules are most likely to fulfill thedesign objectives

To effectively and efficiently propose the most appropriate molecules for synthesis,two key points should be considered by the project team: exploration and exploitation.Exploration uses a molecular diversity measure to efficiently cover the space ofvirtual molecules with an even distribution of known properties This leads to a highconfidence that the entirety of the space is represented with as few molecules asnecessary to demonstrate regions of specific interest This can be achieved using awide variety of diversity selection algorithms [11] Here, the question being asked isthat of the entirety of the chemical space

The coverage of diversity must also be balanced with the synthesis of very closeanalogues tofinesse those properties that are important for that specific project,many of which have been defined already in this chapter Here, the investigation

is directed on small and specific changes, most often a number of single alterationsthat enhance the understanding of the local structure–activity relationship (SAR)

It is with this part of the lead optimization process that bioisosteric ments are most important, as opposed to the diversity design where bioisostericreplacements will not necessarily provide sufficient information about the globalchemical space [13]

replace-Bioisosteric replacement is often considered when the aims are to maintainenzyme potency while optimizing additional properties, such as cellular penetration,solubility, metabolism, toxicity, and so on This principle is often referred to asmultiobjective optimization (MOOP) or multiparameter optimization (MPO) [12].There are many ways in which one can address multiple objectives, but it is important

to understand the landscape of the trade-off surface between each of the important

12j1 Bioisosterism in Medicinal Chemistry

objectives, including an understanding of parameters that may be correlated witheach other (Figure 1.1).

The combination of identifying bioisosteric replacements in a lead moleculetogether with the multiobjective prioritization of virtual molecules in that chemicalseries for synthesis provides the medicinal chemist with the key information formaking design decisions in a therapeutic project The approaches to identifying thesereplacements will be covered in Parts Two and Three of this book, but they can all beapplied in this challenge

to a more functional outlook in terms of biological properties was a major stepforward toward what we today call bioisosterism

Pharmacokinetics

Figure 1.1 Schematic of multiobjective

optimization in a drug discovery project

optimizing potency and pharmacokinetic

properties over time Initially, the emphasis is

on potency in this schematic and significant

improvement was made in this respect As time

progresses and additional characterization of

the molecules is realized, optimizing the pharmacokinetics becomes increasingly important However, the various different parameters should be optimized simultaneously to ensure progression to a clinical candidate.

Bioisosterism is now one of the most important tools that medicinal chemists have

at their disposal Through shrewd application of bioisosteres that have experimentalprecedent or have been identified by theoretical calculations, the medicinal chemist isnow well prepared with highly effective tools that have been demonstrated to be ofgreat utility in therapeutic design programs The remaining chapters in this part willdetail the key theories behind bioisosteres and their replacement

References

1 Meanwell, N.A (2011) Synopsis of some

recent tactical application of bioisosteres

in drug design Journal of Medicinal

Chemistry, 54, 2529–2591.

2 Langmuir, I (1919) Isomorphism,

isosterism and covalence Journal of

the American Chemical Society, 41,

1543 –1559.

3 Grimm, H.G (1925) On construction and

sizes of non-metallic hydrides Zeitschrift

fur Elektrochemie und Angewandte

Physikalische Chemie, 31, 474; 1928, 34,

430; 1934, 47, 553–594.

4 Erlenmeyer, H and Berger, E (1932)

Studies on the significance of structure of

antigens for the production and the

specificity of antibodies Biochemical

Zoology, 252, 22–36.

5 Erlenmeyer, H., Berger, E., and Leo, M.

(1933) Relationship between the structure

of antigens and the specificity of

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14j1 Bioisosterism in Medicinal Chemistry

is often achieved by the medicinal chemists by replacing a functional group withgroups sharing similar physical or chemical properties and maintaining similaractivity, which are defined as bioisosteres We will hereby provide a historicaloverview of the development and evolution of the concepts of isosterism andbioisosterism, followed by a selection of successful examples of bioisosteric mod-ifications reported in the literature.

2.2

Historical Background

The concept of isosterism wasfirst introduced by Langmuir in 1919 to describemolecules that contain the same number and arrangement of electrons and havesimilar physicochemical properties [1] Langmuir identified 21 types of isosteres, afew examples of which are reported in Table 2.1

In 1925, Grimm formulated his “hydride displacement law,” which states that theaddition of a hydride to an atom produces a pseudoatom with the same physicalproperties as those present in the column immediately behind in the periodic table,

as shown in Table 2.2 [2]

The concept of isosterism was later broadened by Erlenmeyer in 1932 to includeelements, ions, or molecules with the same number of electrons at the valence level(Table 2.3) [3] Erlenmeyer stated that elements in the same column of the periodictable are isosteres among themselves and also introduced the concept of electron-ically equivalent rings

Bioisosteres in Medicinal Chemistry, First Edition Edited by Nathan Brown

Ó 2012 Wiley-VCH Verlag GmbH & Co KGaA Published 2012 by Wiley-VCH Verlag GmbH & Co KGaA.

The term bioisosterism was introduced in 1952 by Friedman to describe turally related substances with similar or antagonistic biological properties [4] Thisterm was later broadened by Thornber to include “groups or molecules that havechemical and physical similarities producing broadly similar biologicalproperties” [5].

struc-Finally, in 1970, Alfred Burger classified bioisosteres into classical and sical [6] The former include atoms or groups of the same valence as well as ringequivalents, while the latter are basically those that do notfit the first definition.Several reviews on bioisosteres have been reported in the literature over theyears [7–11], and in the next sections a selection of examples for each of the twocategories will be provided

nonclas-Table 2.1 Examples of isosteres identified by Langmuir.

Table 2.3 Isosteres as defined by Erlenmeyer.

Number of peripheral electrons

One of the most well-known examples of effective replacement of hydrogen withfluorine is observed in the antineoplastic drug 5-fluorouracil (Figure 2.1) Thiscompound is metabolized in vivo to 5-fluoro-20-deoxyuridylic acid (5-fluoro-dUMP),which is the active drug that covalently binds to thymidylate synthase, the enzymeresponsible for the essential conversion in DNA synthesis of uridylic acid tothymidylic acid.

O F

N HN

bioisosteric

replacement

biologicalmetabolism

O OH OPO 32-

Figure 2.1 Bioisosteric H/F replacement in 5-fluorouracil.

adrenoreceptors (a2ARs), which is considered responsible for the side effects Asshown in Figure 2.2, several bivalent bioisosteres of rilmenidine were able tomaintain I1R binding, while losing affinity on the a2-adrenoreceptors, thus reducingundesired side effects.

be unusually less lipophilic than BIRB-796, of comparable potency, and moremetabolically stable in human liver microsomes.

488043 (Figure 2.5), which retained potency against HIV-1 attachment, but had betterpharmacokinetic profilethancompound2andwasthusadvanced inclinicaltrials[15]

Si

NH

NHO

O

SOO

SOO

NR

C O

CN

Modafinil [16] (Figure 2.6) is a widely used drug in the treatment of excessivesleepiness caused by narcolepsy, shift work sleep disorder, and obstructive sleepapnea The mechanism of action of this drug is still uncertain, but it is believed towork in a localized manner using hypocretin, histamine, epinephrine,c-aminobu-tyric acid, and glutamate This compound has an asymmetric sulfoxide group, and it

is currently marketed as a racemate Studies have shown that the sulfone derivative ofmodafinil retains similar activity to the parent compound, as well as not showingincrease in toxicity De Risi et al investigated the replacement of the sulfoxidegroup with a carbonyl to facilitate synthesis and to remove problems associatedwith chirality Compound3 showed a slight loss of activity compared to modafinil,but this was restored when the amide function was modified in compound 4(Figure 2.6)

N

H

O

N O

OO

Figure 2.6 Bioisosteric replacement of modafinil.

20j2 Classical Bioisosteres

O HO

Isosteres of carboxylic acids are often sought to enhance pharmacokinetic erties, by reducing polarity and increasing lipophilicity in order to increase mem-brane permeability In 2010, Hadden et al at Merck Research Laboratories reportedthe synthesis and activity of agonists of the G-protein-coupled receptor bombesinreceptor subtype-3 (BB3), the lack of which has been associated with obesity,hypertension, and diabetes in genetically altered mice [17] Compound5 (Figure 2.7)

prop-is a potent inhibitor of BB3 obtained from a combination of high-throughputscreening and SAR development In order to improve oral bioavailability and brainpenetration, a series of bioisosteres of the carboxylic acid in compound5 were latersynthesized Despite maintaining good in vitro potency and improving oral bioavail-ability, all compounds failed to increase brain penetration: a partially successfulbioisosteric replacement

6

*OH

Hydroxyl Group

In 2005, Wu et al at the Schering-Plough Research Institute reported the synthesisand biological evaluation of phenol bioisosteric analogues of benzazepine D1/D5

antagonists (Figure 2.8) [18] SCH 23390 and SFK 38393 represented a majorbreakthrough in the pharmacology of dopamine receptors, thefirst being a high-affinity and selective D1/D5antagonist and the second being a partial agonist SCH

39166 has undergone several clinical trials, including schizophrenia, cocaine tion, and obesity However, all three compounds present pharmacokinetic issues.For SCH 39166, this liability is mainly due to O-glucuronidation of the phenol andN-dealkylation of the NCH3 group; thus, several heterocyclic rings containing anNH hydrogen bond donor as isosteres of the phenol group were investigated Fourcompounds (Figure 2.9) showed good pharmacokinetic profiles, while maintaininggood antagonist activity on the D1/D5receptors

X¼ O

X¼ NRCatechol bioisosteres are often utilized to overcome pharmacokinetic and toxico-logical issues linked to this moiety Successful examples of bioisosteric replacement

of catechols can be found in catecholamines Benzimidazole analogues of theadrenergic agonists norepinephrine and isoproterenol (Figure 2.10) were

NHO

X

NHO

synthesized by Arnett et al in 1978 to evaluate their activity in adrenergic systems [19].Compound8 (Figure 2.10) is a potent, direct-acting, partial agonist of the a-adren-ergic receptor, while compound9 (Figure 2.10) is a potent b-adrenergic agonist.These benzimidazole derivatives are chemically more stable than the correspondingcatecholamines for which they prove to be valid bioisosteres.

X O

R X KiD1 KiD5

(nM) (nM)

Rat PK (10m/kg po)AUC0-6h (h μg/ml) (ng/ml)Cmax

(h)

BA(%)

NHN

aromatase inhibitor (NSAI) drugs such as vorozole and liarozole have shownadvantages over steroidal drugs in adjuvant treatment Leze et al developed a newclass of NSAI-based 2-, 3-, 5-, and 7-[(aryl)(azolyl)methyl]-1H-indoles as more potentand selective aromatase inhibitors [20] Starting from compound10 (Figure 2.11),which is based on the structures of vorozole and liarozole, and has IC50of 40 nM onCYP19, they introduced modifications on the indolic nitrogen and on the phenyl ring(X) Compounds with X¼ Cl (CYP19 IC50¼ 15 nM) and X ¼ CN (CYP19 IC50¼

19 nM) proved to be equipotent on CYP19 and selective toward CYP17, a oxygenase belonging to the cytochrome P450 enzyme family

NN

N N

ONN

NNNH

N

N

NNHR

N

CN

H3CO

N CN OCH3

Amide isosteres are generally introduced to modulate polarity and bioavailability,while ester isosteres are used to improve metabolism

A recent successful example of amide bioisosterism can be found in the opment of inhibitors of the enzyme cathepsin K, which is involved in osteoclasticbone resorption and is a target for the treatment of osteoporosis [21] Compound

devel-NNNCl

N

N

N

NHNNN

N

Cl

N

NN

X

Figure 2.11 Bioisosteric replacement in nonsteroidal aromatase inhibitors.

24j2 Classical Bioisosteres