Peptidomimetics in Organic and Medicinal Chemistry PDF
Preview Peptidomimetics in Organic and Medicinal Chemistry
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 ©2014JohnWiley&Sons,Ltd Registeredoffice JohnWiley&SonsLtd,TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,UnitedKingdom Fordetailsofourglobaleditorialoffices,forcustomerservicesandforinformationabouthowtoapplyforpermissiontoreuse thecopyrightmaterialinthisbookpleaseseeourwebsiteatwww.wiley.com. TherightoftheauthortobeidentifiedastheauthorofthisworkhasbeenassertedinaccordancewiththeCopyright,Designs andPatentsAct1988. 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Nowarrantymaybecreatedorextendedbyanypromotionalstatementsforthiswork.Neitherthepublishernortheauthorshall beliableforanydamagesarisingherefrom. 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
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