Including case studies of macrocyclic marketed drugs and macrocycles in drug development, this book helps medicinal chemists deal with the synthetic and conceptual challenges of macrocycles in drug discovery efforts.
* Provides needed background to build a program in macrocycle drug discovery -design criteria, macrocycle profiles, applications, and limitations
* Features chapters contributed from leading international figures involved in macrocyclic drug discovery efforts
* Covers design criteria, typical profile of current macrocycles, applications, and limitations
Autorentext
Eric Marsault, PhD, is Professor of Pharmacology and Medicinal Chemistry at the University of
Sherbrooke as well as the Director of the Institut de Pharmacologie de Sherbrooke. Previously,
he was Group Leader, then Director of Medicinal Chemistry at Tranzyme Pharma, where he worked for eight years.
Mark L. Peterson, PhD, is Chief Operating Officer and Corporate Secretary at Cyclenium Pharma, of which he is a member of the founding management / scientific team. He has over 25 years of experience in the biotechnology and pharmaceutical industries.
Inhalt
Foreword xiii
Introduction xv
About the Contributors xix
Part I Challenges Specific to Macrocycles 1
1 Contemporary Macrocyclization Technologies 3
Serge Zaretsky and Andrei K. Yudin
1.1 Introduction 3
1.2 Challenges Inherent to the Synthesis of Macrocycles 3
1.3 Challenges in Macrocycle Characterization 6
1.4 Macrocyclization Methods 8
1.5 Cyclization on the Solid Phase 14
1.6 Summary 17
References 18
2 A Practical Guide to Structural Aspects of Macrocycles (NMR, X?]Ray, and Modeling) 25
David J. Craik, Quentin Kaas and Conan K. Wang
2.1 Background 25
2.2 Experimental Studies of Macrocycles 31
2.3 Molecular Modeling of Macrocyclic Peptides 38
2.4 Summary 46
Acknowledgments 47
References 47
3 Designing Orally Bioavailable Peptide and Peptoid Macrocycles 59
David A. Price, Alan M. Mathiowetz and Spiros Liras
3.1 Introduction 59
3.2 Improving Peptide Plasma Half?]Life 60
3.3 Absorption, Bioavailability, and Methods for Predicting Absorption 61
3.4 In Silico Modeling 70
3.5 Future Directions 71
References 72
Part II Classes of Macrocycles and Their Potential for Drug Discovery 77
4 Natural and Nature?]Inspired Macrocycles: A Chemoinformatic Overview and Relevant Examples 79
Ludger A. Wessjohann, Richard Bartelt and Wolfgang Brandt
4.1 Introduction to Natural Macrocycles as Drugs and Drug Leads 79
4.2 Biosynthetic Pathways, Natural Role, and Biotechnological Access 79
4.3 QSAR and Chemoinformatic Analyses of Common Features 84
4.4 Case Studies: Selected Natural Macrocycles of Special Relevance in Medicinal Chemistry 88
References 91
5 Bioactive and Membrane?]Permeable Cyclic Peptide Natural Products 101
Andrew T. Bockus and R. Scott Lokey
5.1 Introduction 101
5.2 Structural Motifs and Permeability of Cyclic Peptide Natural Products 101
5.3 Conformations of Passively Permeable Bioactive Cyclic Peptide Natural Products 103
5.4 Recently Discovered Bioactive Cyclic Peptide Natural Products 108
5.5 Conclusions 125
References 125
6 Chemical Approaches to Macrocycle Libraries 133
Ziqing Qian, Patrick G. Dougherty and Dehua Pei
6.1 Introduction 133
6.2 Challenges Associated with Macrocyclic One?]Bead?]One-Compound Libraries 134
6.3 Deconvolution of Macrocyclic Libraries 134
6.4 Peptide?]Encoded Macrocyclic Libraries 136
6.5 DNA?] Encoded Macrocyclic Libraries 142
6.6 Parallel Synthesis of Macrocyclic Libraries 142
6.7 Diversity?] Oriented Synthesis 145
6.8 Perspective 147
6.9 Conclusion 149
References 150
7 Biological and Hybrid Biological/Chemical Strategies in Diversity Generation of Peptidic Macrocycles 155
Francesca Vitali and Rudi Fasan
7.1 Introduction 155
7.2 Cyclic Peptide Libraries on Phage Particles 155
7.3 Macrocyclic Peptide Libraries via In Vitro Translation 166
7.4 Emerging Strategies for the Combinatorial Synthesis of Hybrid Macrocycles In Vitro and in Cells 171
7.5 Comparative Analysis of Technologies 175
7.6 Conclusions 178
References 178
8 Macrocycles for ProteinProtein Interactions 185
Eilidh Leitch and Ali Tavassoli
8.1 Introduction 185
8.2 Library Approaches to Macrocyclic PPI Inhibitors 186
8.3 Structural Mimicry 192
8.4 Multi?] Cycles for PPIs 197
8.5 The Future for Targeting PPIs with Macrocycles 197
References 200
Part III The Synthetic Toolbox for Macrocycles 205
9 Synthetic Strategies for Macrocyclic Peptides 207
Éric Biron, Simon Vezina?]Dawod and Fran&...