Peptidomimetics in Organic and Medicinal Chemistry

320 Pages·2014·14.12 MB·English

by  Antonio Guarna

Peptidomimetics in Organic and Medicinal
Chemistry

Peptidomimetics
in Organic and Medicinal
Chemistry
The Art of Transforming Peptides in Drugs
ANDREA TRABOCCHI
Department of Chemistry “Ugo Schiff”, University of Florence, Italy
ANTONIO GUARNA
Department of Chemistry “Ugo Schiff”, University of Florence, Italy
Thiseditionfirstpublished2014
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LibraryofCongressCataloging-in-PublicationData
Trabocchi,Andrea,author.
Peptidomimeticsinorganicandmedicinalchemistry/Dr.AndreaTrabocchiandProfessorAntonio
Guarna.
pagescm
Includesbibliographicalreferencesandindex.
ISBN978-1-119-95060-8(hardback)
1.Peptidedrugs.2.Proteins–Therapeuticuse.3.Drugs–Design.I.Guarna,Antonio,author.II.Title.
RS431.P38T732014
615.1′9–dc23
2013048681
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
ISBN:9781119950608
Typesetin10/12ptTimesLTStdbyLaserwordsPrivateLimited,Chennai,India
1 2014
Dedicatedtoourfamilies:
NicolettaandTommaso
Lory,Francesco,SaraandTommaso

Contents
Preface xiii
Abbreviations xvii
PART I The Basics of Peptidomimetics 1
1. TheBasicsofPeptidomimetics 3
1.1 Introduction 3
1.2 DefinitionandClassification 5
1.3 StrategicApproachestoPeptidomimeticDesign 7
1.3.1 ModificationofAminoAcids 8
1.3.2 CompoundswithGlobalRestrictions 9
1.3.3 MolecularScaffoldsMimickingthePeptidicBackbone 10
1.4 SuccessfulExamplesofPeptidomimeticDrugs 12
1.4.1 ACEInhibitors 13
1.4.2 ThrombinInhibitors 13
1.5 Conclusion 16
References 16
2. SyntheticApproachestowardsPeptidomimeticDesign 19
2.1 Introduction 19
2.2 LocalModifications 20
2.2.1 SingleAminoAcidModifications 23
2.2.2 DipeptideIsosteres 26
2.2.3 Retro-inversoPeptides 29
2.2.4 N-MethylationofPeptides 30
2.2.5 Azapeptides 31
2.2.6 Peptoids 31
2.3 GlobalRestrictionsthroughCyclicPeptidomimetics 32
2.4 PeptidomimeticScaffolds 34
2.5 Conclusions 35
References 35
viii Contents
PART II Synthetic Methods and Molecules 37
3. PeptidomimeticBioisosteres 39
3.1 Introduction 39
3.2 PeptideBondIsosteres 40
3.2.1 Thioamides 41
3.2.2 Esters 41
3.2.3 AlkenesandFluoroalkenes 41
3.2.4 Transition-StateIsosteres 42
3.3 Side-ChainIsosteres 45
3.3.1 GuanidineIsosteresinArgininePeptidomimetics 45
3.3.2 IsosteresofAsparticAcidandGlutamicAcid 49
3.3.3 Tetheredα-AminoAcids:Constrainingtheχ-Space 53
3.4 DipeptideIsosteres 59
3.4.1 δ-AminoAcids 63
3.5 TripeptideIsosteres 67
3.6 Conclusion 68
References 69
4. Solid-PhaseSynthesisandCombinatorialApproachestoPeptidomimetics 75
4.1 Introduction 75
4.2 Solid-PhaseSynthesisofPeptidomimetics 76
4.2.1 Scaffoldsfromα-AminoAcids 76
4.2.2 ScaffoldsfromAminoAldehydeIntermediates 85
4.2.3 Pyrrolidine-ContainingScaffolds 89
4.3 Conclusion 94
References 95
5. ClickChemistry:TheTriazoleRingasaPrivilegedPeptidomimetic
Scaffold 99
5.1 Introduction 99
5.1.1 CuAACReaction 100
5.1.2 TriazoleRingasaPeptidomimeticIsostere 101
5.2 Triazole-ContainingPeptidomimeticsElaboratedthrough‘Click
Chemistry’ 102
5.2.1 Macrocycles 102
5.2.2 OligomersandFoldamers 107
5.3 RelevantApplicationsinDrugDiscovery 110
5.3.1 AChEInhibitors 110
5.3.2 HIVProteaseInhibitors 111
5.3.3 MMPInhibitors 114
5.3.4 IntegrinLigands 115
5.4 Conclusions 118
Acknowledgements 119
References 119