Antonio Guarna, Andrea Trabocchi

Peptidomimetics in Organic and Medicinal Chemistry (eBook, ePUB)

The Art of Transforming Peptides in Drugs

• Format: ePub

Produktbeschreibung

A peptidomimetic is a small protein-like chain designed to mimic a peptide with adjusted molecular properties such as enhanced stability or biological activity. It is a very powerful approach for the generation of small-molecule-based drugs as enzyme inhibitors or receptor ligands. Peptidomimetics in Organic and Medicinal Chemistry outlines the concepts and synthetic strategies underlying the building of bioactive compounds of a peptidomimetic nature. Topics covered include the chemistry of unnatural amino acids, peptide- and scaffold-based peptidomimetics, amino acid-side chain isosteres, backbone isosteres, dipeptide isosteres, beta-turn peptidomimetics, proline-mimetics as turn inducers, cyclic scaffolds, amino acid surrogates, and scaffolds for combinatorial chemistry of peptidomimetics. Case studies in the hit-to-lead process, such as the development of integrin ligands and thrombin inhibitors, illustrate the successful application of peptidomimetics in drug discovery.

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Produktdetails

• Verlag: John Wiley & Sons
• Seitenzahl: 312
• Erscheinungstermin: 14. März 2014
• Englisch
• ISBN-13: 9781118683149
• Artikelnr.: 40615268

Autorenporträt

Andrea Trabocchi Department of Chemistry "Ugo Schiff", University of Florence, Italy Antonio Guarna Department of Chemistry "Ugo Schiff", University of Florence, Italy

Inhaltsangabe

Preface xiii Abbreviations xvii PART I The Basics of Peptidomimetics 1 1.
The Basics of Peptidomimetics 3 1.1 Introduction 3 1.2 Definition and
Classification 5 1.3 Strategic Approaches to Peptidomimetic Design 7 1.3.1
Modification of Amino Acids 8 1.3.2 Compounds with Global Restrictions 9
1.3.3 Molecular Scaffolds Mimicking the Peptidic Backbone 10 1.4 Successful
Examples of Peptidomimetic Drugs 12 1.4.1 ACE Inhibitors 13 1.4.2 Thrombin
Inhibitors 13 1.5 Conclusion 16 References 16 2. Synthetic Approaches
towards Peptidomimetic Design 19 2.1 Introduction 19 2.2 Local
Modifications 20 2.2.1 Single Amino Acid Modifications 23 2.2.2 Dipeptide
Isosteres 26 2.2.3 Retro-inverso Peptides 29 2.2.4 N-Methylation of
Peptides 30 2.2.5 Azapeptides 31 2.2.6 Peptoids 31 2.3 Global Restrictions
through Cyclic Peptidomimetics 32 2.4 Peptidomimetic Scaffolds 34 2.5
Conclusions 35 References 35 PART II Synthetic Methods and Molecules 37 3.
Peptidomimetic Bioisosteres 39 3.1 Introduction 39 3.2 Peptide Bond
Isosteres 40 3.2.1 Thioamides 41 3.2.2 Esters 41 3.2.3 Alkenes and
Fluoroalkenes 41 3.2.4 Transition-State Isosteres 42 3.3 Side-Chain
Isosteres 45 3.3.1 Guanidine Isosteres in Arginine Peptidomimetics 45 3.3.2
Isosteres of Aspartic Acid and Glutamic Acid 49 3.3.3 Tethered alpha-Amino
Acids: Constraining the chi-Space 53 3.4 Dipeptide Isosteres 59 3.4.1
delta-Amino Acids 63 3.5 Tripeptide Isosteres 67 3.6 Conclusion 68
References 69 4. Solid-Phase Synthesis and Combinatorial Approaches to
Peptidomimetics 75 4.1 Introduction 75 4.2 Solid-Phase Synthesis of
Peptidomimetics 76 4.2.1 Scaffolds from alpha-Amino Acids 76 4.2.2
Scaffolds from Amino Aldehyde Intermediates 85 4.2.3 Pyrrolidine-Containing
Scaffolds 89 4.3 Conclusion 94 References 95 5. Click Chemistry: The
Triazole Ring as a Privileged Peptidomimetic Scaffold 99 5.1 Introduction
99 5.1.1 CuAAC Reaction 100 5.1.2 Triazole Ring as a Peptidomimetic
Isostere 101 5.2 Triazole-Containing Peptidomimetics Elaborated through
'Click Chemistry' 102 5.2.1 Macrocycles 102 5.2.2 Oligomers and Foldamers
107 5.3 Relevant Applications in Drug Discovery 110 5.3.1 AChE Inhibitors
110 5.3.2 HIV Protease Inhibitors 111 5.3.3 MMP Inhibitors 114 5.3.4
Integrin Ligands 115 5.4 Conclusions 118 Acknowledgements 119 References
119 6. Peptoids 123 6.1 Introduction and Basics of Peptoids 123 6.2
Synthetic Methods 126 6.3 Macrocyclic Peptoids 129 6.4 Conformational
Analysis of Folded Peptoids 130 6.5 Application of Peptoids as
Antimicrobial Peptidomimetics 132 6.6 Conclusions 134 References 134 7.
Sugar Amino Acids 137 7.1 Introduction 137 7.2 alpha-SAAs 138 7.2.1
Furanoid alpha-SAAs 138 7.2.2 Pyranoid alpha-SAAs 142 7.3 ß-SAAs 144 7.3.1
Furanoid ß-SAAs 144 7.3.2 Pyranoid ß-SAAs 147 7.4 gamma-SAAs 148 7.5
delta-SAAs 150 7.5.1 Furanoid delta-SAAs 150 7.5.2 Pyranoid delta-SAAs 154
7.6 Representative Applications in Medicinal Chemistry 159 7.7 Conclusions
162 References 162 8. Cyclic alpha-Amino Acids as Proline Mimetics 165 8.1
Introduction 165 8.2 Cyclic alpha-Amino Acids 166 8.2.1 3-Substituted
Proline Derivatives 167 8.2.2 4-Substituted Proline Derivatives 168 8.2.3
5-Substituted Proline Derivatives 169 8.2.4 Other Heterocyclic Proline
Analogues 171 8.3 Bicyclic alpha-Amino Acids 174 8.3.1 ß/gamma-Ring
Junction 175 8.3.2 alpha/gamma-Ring Junction 178 8.3.3 gamma/delta-Ring
Junction 179 8.3.4 alpha/delta-Ring Junction 180 8.3.5 ß/delta-Ring
Junction 182 8.3.6 N/ß-Ring Junction 183 8.3.7 Pipecolic-Based Bicyclic
alpha-Amino Acids 183 8.3.8 Morpholine-Based Bicyclic alpha-Amino Acids 187
8.4 Conclusions 189 References 189 9. beta-Turn Peptidomimetics 191 9.1
Introduction 191 9.2 Definition and Classification of ß-Turns 192 9.3
Conformational Analysis 194 9.4 ß-Turn Peptidomimetics 196 9.4.1 Proline
Analogues in ß-Turn Peptidomimetics 197 9.4.2 delta-Amino Acids as
Reverse-Turn Inducers 200 9.4.3 Molecular Scaffolds as ß-Turn
Peptidomimetics 209 9.5 Conclusions 214 References 215 10. Peptidomimetic
Foldamers 219 10.1 Introduction 219 10.2 Classification 220 10.3 Peptoids
221 10.4 ß-Peptides: First Systematic Conformational Studies 221 10.5
Hybrid Foldamers 226 10.6 From Structural to Functional Foldamers 227
10.6.1 Peptoids as Foldameric Antimicrobial Peptidomimetics 227 10.6.2
Foldamers Targeting Bcl-xL Antiapoptotic Proteins 227 10.7 Conclusions 228
References 228 PART III Applications in Medicinal Chemistry 231 11. Case
Study 1: Peptidomimetic HIV Protease Inhibitors 233 11.1 Introduction 233
11.2 The HIV-1 Virus 233 11.2.1 HIV-1 Protease 234 11.3 Antiretroviral
Therapy 238 11.4 Drug Resistance 239 11.4.1 Mechanisms of Resistance to
Protease Inhibitors 239 11.5 HIV-1 Protease Inhibitors 240 11.5.1
Transition-State Analogues 240 11.5.2 Peptidomimetic Drugs 241 11.5.3
Next-Generation Cyclic Peptidomimetic Inhibitors 245 11.6 Conclusions 255
Acknowledgements 255 References 256 12. Case Study 2: Peptidomimetic
Ligands for alpha v beta 3 Integrin 259 12.1 Introduction 259 12.2
Peptide-Based Peptidomimetic Integrin Ligands 262 12.3 Scaffold-Based
Peptidomimetic Integrin Ligands 270 12.4 Conclusions 280 References 280
Index 283