Methods and Principles in Medicinal Chemistry

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List of Contributors

Frank H. Allen

Cambridge Crystallographic Data Centre (CCDC)

12 Union Road

Cambridge CB2 1EZ

UK

Karam B. Alsayyed Ahmed

University of North Carolina at Greensboro

Department of Chemistry & Biochemistry

Center for Drug Design

Greensboro, NC 27410

SUA

Pedro J. Ballester

European Bioinformatics Institute

Wellcome Trust Genome Campus

Hinxton, Cambridge CB10 1SD

UK

David A. Bardwell

Cambridge Crystallographic Data Centre (CCDC)

12 Union Road

Cambridge CB2 1EZ

UK

Caterina Barillari

The Institute of Cancer Research

Cancer Research UK Cancer Therapeutics Unit

15 Cotswold Road

Sutton SM2 5NG

UK

Nicholas P. Barton

GlaxoSmithKline Pharmaceuticals

New Frontiers Science Park (North)

Coldharbour Road

Harlow, Essex CM15 5AD

UK

Michael J. Bodkin

Eli Lilly Limited

Erl Wood Manor

Windlesham, Surrey GU20 6PH

UK

J. Phillip Bowen

University of North Carolina at Greensboro

Department of Chemistry & Biochemistry

Center for Drug Design

Greensboro, NC 27410

USA

and

Mercer University

College of Pharmacy and Health Sciences

Department of Pharmaceutical Sciences

3001 Mercer University Drive

Atlanta, GA 30341

USA

Nathan Brown

The Institute of Cancer Research

Cancer Research UK Cancer Therapeutics Unit

15 Cotswold Road

Sutton SM2 5NG

UK

Ian J. Bruno

Cambridge Crystallographic Data Centre (CCDC)

12 Union Road

Cambridge CB2 1EZ

UK

Mike Devereux

University of Basel

Klingelbergstrasse 80

4056 Basel

Switzerland

Peter Ertl

Novartis Institutes for BioMedical Research

Novartis Campus

4056 Basel

Switzerland

Marcus Gastreich

BioSolveIT

An der Ziegelei 79

53757 St. Augustin

Germany

Valerie J. Gillet

The University of Sheffield

Information School

Regent Court

211 Portobello

Sheffield S1 4DP

UK

Colin R. Groom

Cambridge Crystallographic Data Centre (CCDC)

12 Union Road

Cambridge CB2 1EZ

UK

Julian Hayward

Digital Chemistry Ltd

30 Kiveton Lane

Todwick, Sheffield S26 1HL

UK

John W. Liebeschuetz

Cambridge Crystallographic Data Centre (CCDC)

12 Union Road

Cambridge CB2 1EZ

UK

Nicholas A. Meanwell

Bristol-Myers Squibb Pharmaceutical Research and Development

Department of Medicinal Chemistry

5 Research Parkway

Wallingford, CT 06492

USA

David Millan

Sandwich Laboratories

Pfizer Global Research and Development

Ramsgate Road

Sandwich, Kent CT13 9NJ

UK

James E. J. Mills

Sandwich Laboratories

Pfizer Global Research and Development

Ramsgate Road

Sandwich, Kent CT13 9NJ

UK

Tjelvar J. Olsson

Cambridge Crystallographic Data Centre (CCDC)

12 Union Road

Cambridge CB2 1EZ

UK

George Papadatos

Eli Lilly Limited

Erl Wood Manor

Windlesham, Surrey GU20 6PH

UK

Paul L.A. Popelier

University of Manchester

Manchester Interdisciplinary Biocentre (MIB)

131 Princess Street

Manchester M1 7DN

UK

and

University of Manchester

School of Chemistry

Oxford Road

Manchester M13 9PL

UK

Matthias Rarey

ZBH University of Hamburg

Bundesstrasse 43

20146 Hamburg

Germany

Gisbert Schneider

ETH Zurich

Institute of Pharmaceutical Sciences

8093 Zurich

Switzerland

Jason Shanley

Abbott Laboratories

Global Pharmaceutical Research and Development

Department of Structural Biology

100 Abbott Park Road

Abbott Park, IL 60031

USA

Dennis A. Smith

Sandwich Laboratories

Pfizer Global Research and Development

Ramsgate Road

Sandwich, Kent CT13 9NJ

UK

Kent D. Stewart

Abbott Laboratories

Global Pharmaceutical Research and Development

Department of Structural Biology

100 Abbott Park Road

Abbott Park, IL 60031

USA

István Ujváry

iKem BT

Búza u. 32

1033 Budapest

Hungary

Peter Willett

University of Sheffield

Information School

Sheffield S1 4DP

UK

Preface

Bioisosteric replacement of substituents, ring atoms, linkers, and other groups aims to generate chemical substitutes with related biological properties, in the hope that the new analogues may have somewhat better properties. Such replacements are the toolbox of medicinal chemists to optimize their lead structures with respect to lipophilicity, solubility, activity, selectivity, absorption, metabolism, and lack of toxic and other side effects. Whenever an analogue with some improved properties is observed, the new compound is taken as the starting point for further modification. In this evolutionary procedure, either a preclinical or a clinical candidate results or the project has to be terminated, without success. Whereas the whole process quite often follows a trial and error procedure, certain empirical rules developed in medicinal chemistry. Very simple ones are, for example, the replacement of a hydrogen atom in the para-position of a benzene ring, to avoid rapid metabolic degradation, or, on the other hand, the introduction of an aromatic methyl group instead of a chlorine atom, to avoid too long biological half-life. More sophisticated rules exist for modification of the ligands of certain targets, for example, proteases or kinases.

The organization of this book follows a logical sequence, starting with Part One on the principles of bioisosterism, including an introductory chapter, and chapters on classical bioisosteres in medicinal chemistry and the logical but often surprising consequences of bioisosteric replacement. Part Two presents a database on bioisosteres and bioanalogues and discusses the search for bioisosteres, using the Cambridge Structure Database of 3D structures of small molecules, as well as the mining of bioisosteric pairs. Part Three presents methods to identify bioisosteres under the aspect of physicochemical properties, molecular topology, molecular shape, and protein 3D structures. Part Four describes a computer program for drug design, using medicinal chemistry rules, discusses the bioisosteric modification of a receptor antagonist, and ends with a concluding chapter on perspectives from medicinal chemistry.

Whereas some reviews on bioisosteres are found in the literature, as well as chapters in medicinal chemistry books, no dedicated monograph on bioisosteres has been published so far. Thus, we are very grateful to Nathan Brown for editing such a book, which will help novices in the field as well as experienced scientists to manage lead structure optimization in an even more rational manner. In addition, we are very much indebted to Frank Weinreich and Heike Nöthe, both at Wiley-VCH. Their 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 this excellent collection of monographs on various topics, all related to drug research.

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 II

William Shakespeare

The essence of design is the identification of appropriate constituents and their careful arrangement in sympathy with the requirements of the desired object. The same principles apply in drug design, where the components are elements and elemental groups, and their arrangement is achieved through the synthetic organic chemistry 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 identification and 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 a time when its application has become a formal process. There are now many information sources and design tools available to assist the medicinal chemist in the identification of relevant bioisosteres.

The first part of this book covers the historical aspects of bioisosterism, from its founding principles of isosterism from Langmuir through defined sets of classical isosteres and bioisosteres, to the potential consequences of bioisosteric replacement in context.

A considerable amount of knowledge has been collated in recent years, in large molecular databases with metadata that can be analyzed and brought to bear in bioisosteric replacement. Knowledge-based methods form the second part, covering experimentally determined bioisosteric replacements from the medicinal chemistry literature; small-molecule crystal identification of bioisosteres; and mining unknown bioisosteres from these databases through the application of recently developed 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 of different representations. A number of computational approaches to bioisosteric replacement are covered in chapters on physicochemical properties, molecular topology, molecular shape, and the use of protein structure information. Each chapter covers many common methods and overviews of when best to apply these methods, and where they have been successfully applied.

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

My sincere wish is that you enjoy reading this book as much as I did working with 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 this book together.

London, 2012

Nathan Brown

Part One

Principles

Chapter 1

Bioisosterism in Medicinal Chemistry

Nathan Brown

1.1 Introduction

One of the key challenges for the medicinal chemist today is the modulation and mediation 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 effectively while also ensuring that it satisfies necessary safety requirements. One of the most significant approaches to assist in efficiently navigating the available chemistry space is that of bioisosteric replacement.

This book, the first dedicated solely to the subject of bioisosterism, covers the field from the very beginning to its development as a reliable and well-used approach to assist in drug design. This book is split into four parts. The first part covers the principles and theory behind isosterism and bioisosterism. The second part investigates methods that apply knowledge bases of experimental data from a variety of sources to assist in decision making. The third part reports on the four main computational approaches to bioisosteric identification and replacement using molecular properties, topology, shape, and protein structure. This book concludes with real-world examples of bioisosterism in application and a collection of reflections and perspectives on bioisosteric identification and replacement from many of the current leaders in the field.

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

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 early isosterism work was on the electronic configuration of atoms. Langmuir used experiment to identify the correspondence between the physical properties of different substances. Langmuir, in accordance with the octet rule where atoms will often combine to have eight electrons in their valence shells, compared the number and arrangement of electrons between nitrogen, carbon monoxide, and the cyanogen ion and 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 dioxide when taking experimental data from Landolt–Börnstein's tables and Abegg's handbook ().

Experimental data from Landolt–Börnstein's tables and Abegg's handbook for nitrous oxide (N₂O) and carbon dioxide (CO₂)

However, Langmuir identified one distinct property that is substantially different between 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 being “abnormally sensitive to even slight differences in structure.”

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

“Comolecules are thus isosteric if they contain the same number and arrangement of electrons. The comolecules of isosteres must, therefore, contain the same number of atoms. The essential differences between isosteres are confined to the charges on the nuclei of the constituent atoms. Thus in carbon dioxide the charges on the nuclei of the carbon and oxygen atoms are 6 and 8, respectively, and there are 2 × 8 + 6 = 22 electrons in the molecule. In nitrous oxide the number of charges on the nitrogen nuclei is 7, but the total number of electrons in the molecule is again 2 × 7 + 8 = 22. The remarkable similarity of the physical properties of these two substances proves that their electrons are arranged in the same manner.”

The list of isosteres that Langmuir described in 1919 is given in . Langmuir extended his concept of isosterism to predicting likely crystal forms using sodium and fluorine ions as exemplars, these having been solved by William Henry Bragg and William Lawrence Bragg – father and son who were together awarded the Nobel Prize for Physics in 1915. Since the magnesium and oxygen ions are isosteric with the sodium and fluorine ions, it follows that magnesium oxide will have a crystal structure that is identical to that of sodium fluoride.

List of isosteres defined by Langmuir in 1919.

In 1925, H.G. Grimm [3] extended the concept of isosterism, introduced by Langmuir, with Grimm's hydride displacement law:

“Atoms anywhere up to four places in the periodic system before an inert gas change their properties by uniting with one to four hydrogen atoms, in such a manner that the resulting combinations behave like pseudoatoms, which are similar to elements in the groups one to four places, respectively, to their 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.

Beginning in 1932, Friedrich Erlenmeyer [4, 5] extended the concepts from Grimm further and the first applications of isosterism to biological systems. Erlenmeyer redefined isosteres as:

“. . .elements, molecules or ions in which the peripheral layers of electrons may be considered identical.”

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

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

1.3 Bioisosterism

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

A number of classical bioisosteric examples are provided in that illustrate typical replacements possible in each of these five groups.

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

Monovalent bioisosteres

F, H

OH, NH

F, OH, NH, or CH3 for H

SH, OH

Cl, Br, CF3

Divalent bioisosteres

–C=S, –C=O, –C=NH, –C=C–

Trivalent atoms or groups

–CH=, –N=

–P=, –As=

Tetrasubstituted atoms

Ring equivalents

However, more recent definitions of isosterism, and more specifically bioisosterism, relax these constraints and permit bioisosteric pairings between moieties that do not necessarily contain the same number of atoms. Specifically, nonclassical bioisosteres include the addition of the following two groups:

The origins of classical isosterism focused largely on the electronic similarity of groups rather than their functional similarity. As investigation into the field progressed, it became obvious that these very defined rules on isosterism, although powerful, were restrictive in particular to medicinal chemistry. The addition of the latter two groups for nonclassical bioisosteres permitted the mimicking of spatial arrangements, electronic properties, or another physicochemical property that is important for biological activity.

In extending and broadening the purer rules of classical isosterism, two scientists are credited with progressing the field of bioisosterism: Friedman and Thornber. In 1951, Friedman [7] provided the first definition closest to what we call bioisosterism today:

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

With this definition, the generalization of what constitutes bioisosterism was formed. However, this definition really only considers the macromolecular recognition of bioisosteres, which is of course highly important, but largely ignores the specifics of the numerous other physicochemical properties that are optimized in a medicinal chemistry project. Friedman's definition was followed in 1979 with the much less specific definition from Thornber [8] of bioisosteres and nonclassical bioisosteres:

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

At first reading, this definition looks somewhat similar to Friedman's, but it is the relevant importance of chemical and physical similarities that differentiates this from Friedman's definition. In addition to this definition, Thornber also defined eight parameters that could be considered in making an alteration to a structural moiety to elicit a bioisosteric pairing:

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

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

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

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

Burger's definition succinctly defines bioisosteres including all of the aforementioned extensions defined by other scientists in the field. The next section focuses on the specific improvements in lead optimization that can be gained by prudent application 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 lead optimization stage of a drug discovery project. Once a lead molecule has been identified, the medicinal chemist is faced with the considerable challenge of making small, defined changes to an identified core structure (also chemotype or scaffold) by the addition or substitution of functional groups to test specific hypotheses. While the challenge of scaffold hopping (the replacement of the functional or specific exit geometries of a molecular scaffold) is important, this challenge will only be considered 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 been identified, and also chemical handles, to permit the synthesis of many analogues, the project team will identify substituents that are potential bioisosteric replacements using a number of different methods. Many of these methods will be discussed in Parts Two and Three of this book from the literature and in silico modeling approaches, respectively. Southall and Ajay [10] reported a number of common medicinal chemistry bioisosteric replacements from kinase drug candidates (). 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].

Common replacements in medicinal chemistry taken from the literature [10]

1.4.2 Structure-Based Drug Design

It is becoming increasingly common that protein–ligand cocrystal structures are available to assist early on in a drug design project. The inclusion of structural information allows the design of molecules that take into account what may or may not be tolerated in a particular position, according to the conformations of key protein structure residues. This is in contrast to only using the information within the ligands that have already been synthesized and tested. The latter can lead to the assumption that the bioisosteric replacement must have the same bulk properties as the original group or, more frequently, lead to inefficiency in the design process through the unnecessary synthesis of molecules that function only to probe functional group tolerability at different positions on a molecule.

The application of protein structures to suggest bioisosteric replacements will be covered more fully in Chapter 10.

1.4.3 Multiobjective Optimization

As has been discussed previously, lead optimization involves the separate, although sometimes simultaneous, optimization of multiple parameters. When considering replacement of key functional groups around a common molecular scaffold, the chemical space of potential molecules that could be synthesized (assuming no issues in terms of synthetic accessibility, stability, etc.) is the product of the number of feasible 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 realize the 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 the design 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 of virtual molecules with an even distribution of known properties. This leads to a high confidence that the entirety of the space is represented with as few molecules as necessary to demonstrate regions of specific interest. This can be achieved using a wide variety of diversity selection algorithms [11]. Here, the question being asked is that of the entirety of the chemical space.

The coverage of diversity must also be balanced with the synthesis of very close analogues to finesse 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 alterations that enhance the understanding of the local structure–activity relationship (SAR). It is with this part of the lead optimization process that bioisosteric replacements are most important, as opposed to the diversity design where bioisosteric replacements will not necessarily provide sufficient information about the global chemical space [13].

Bioisosteric replacement is often considered when the aims are to maintain enzyme potency while optimizing additional properties, such as cellular penetration, solubility, metabolism, toxicity, and so on. This principle is often referred to as multiobjective 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 objectives, including an understanding of parameters that may be correlated with each other ().

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.

The combination of identifying bioisosteric replacements in a lead molecule together with the multiobjective prioritization of virtual molecules in that chemical series for synthesis provides the medicinal chemist with the key information for making design decisions in a therapeutic project. The approaches to identifying these replacements will be covered in Parts Two and Three of this book, but they can all be applied in this challenge.

1.5 Conclusions

The origins of isosterism have been traced back to the early twentieth century, most notably in the work of Langmuir, which also gave the concept its name. The extension of isosterism through Grimm and Erlenmeyer paved the way to the definition of bioisosterism, largely promulgated by Friedman and Thornber. Moving from a definition of isosterism that focused specifically on the electronic makeup of isosteres to a more functional outlook in terms of biological properties was a major step forward toward what we today call bioisosterism.

Bioisosterism is now one of the most important tools that medicinal chemists have at their disposal. Through shrewd application of bioisosteres that have experimental precedent or have been identified by theoretical calculations, the medicinal chemist is now well prepared with highly effective tools that have been demonstrated to be of great utility in therapeutic design programs. The remaining chapters in this part will detail 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 antibodies. Helvetica Chimica Acta, 16, 733–738.

6. Lemke, T.L. and Williams, D.A. (2007) Foye's Principles of Medicinal Chemistry, 6th edn, Lippincott Williams & Wilkins, Baltimore, MD.

7. Friedman, H.L. (1951) Influence of isosteric replacements upon biological activity. NAS-NRS Publication No. 206, NAS-NRS, Washington, DC, pp. 295–358.

8. Thornber, C.W. (1979) Isosterism and molecular modification in drug design. Chemical Society Reviews, 8, 563–580.

9. Burger, A. (1991) Isosterism and bioisosterism in drug design. Progress in Drug Research, 37, 288–362.

9. Southall, N.T. and Ajay (2006) Kinase patent space visualization using chemical replacements. Journal of Medicinal Chemistry, 49, 2103–2109.

11. Gillet, V.J. (2011) Diversity selection algorithms. Wiley Interdisciplinary Reviews: Computational Molecular Science, 1, 580–589.

12. Nicolaou, C.A., Brown, N., and Pattichis, C.K. (2007) Molecular optimization using multi-objective methods. Current Opinion in Drug Discovery & Development, 10, 316–324.

13. Brown, N. and Lewis, R.A. (2006) Exploiting QSAR methods in lead optimization. Current Opinion in Drug Discovery & Development, 9, 419–424.

14. Ciapetti, P. and Giethlen, B. (2008) Molecular variations based on isosteric replacements, in The Practice of Medicinal Chemistry, 3rd edn (ed. C.G. Wermuth), Elsevier.

15. DiMasi, J. and Faden, L.B. (2011) Competitiveness in follow-on drug R&D: a race of imitation? Nature Reviews Drug Discovery, 10, 23–27.

16. Langdon, S.R., Ertl, P., and Brown, N. (2010) Bioisosteric replacement and scaffold hopping in lead generation and optimization. Molecular Informatics, 29, 366–385.

17. Patani, G.A. and LaVoie, E.J. (1996) Bioisosterism: a rational approach in drug design. Chemical Reviews, 96, 3147–3176.

18. Wermuth, C.G. (2006) Similarity in drugs: reflections on analogue design. Drug Discovery Today, 11, 348–354.