Practical Medicinal Chemistry with Macrocycles

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.

• Foreword xiiiIntroduction xvAbout the Contributors xixPart I Challenges Specific to Macrocycles 11 Contemporary Macrocyclization Technologies 3Serge Zaretsky and Andrei K. Yudin1.1 Introduction 31.2 Challenges Inherent to the Synthesis of Macrocycles 31.3 Challenges in Macrocycle Characterization 61.4 Macrocyclization Methods 81.5 Cyclization on the Solid Phase 141.6 Summary 17References 182 A Practical Guide to Structural Aspects of Macrocycles (NMR, X]Ray, and Modeling) 25David J. Craik, Quentin Kaas and Conan K. Wang2.1 Background 252.2 Experimental Studies of Macrocycles 312.3 Molecular Modeling of Macrocyclic Peptides 382.4 Summary 46Acknowledgments 47References 473 Designing Orally Bioavailable Peptide and Peptoid Macrocycles 59David A. Price, Alan M. Mathiowetz and Spiros Liras3.1 Introduction 593.2 Improving Peptide Plasma Half]Life 603.3 Absorption, Bioavailability, and Methods for Predicting Absorption 613.4 In Silico Modeling 703.5 Future Directions 71References 72Part II Classes of Macrocycles and Their Potential for Drug Discovery 774 Natural and Nature]Inspired Macrocycles: A Chemoinformatic Overview and Relevant Examples 79Ludger A. Wessjohann, Richard Bartelt and Wolfgang Brandt4.1 Introduction to Natural Macrocycles as Drugs and Drug Leads 794.2 Biosynthetic  Pathways, Natural Role, and Biotechnological Access 794.3 QSAR and Chemoinformatic Analyses of Common Features 844.4 Case Studies: Selected Natural Macrocycles of Special Relevance in Medicinal Chemistry 88References 915 Bioactive and Membrane]Permeable Cyclic Peptide Natural Products 101Andrew T. Bockus and R. Scott Lokey5.1 Introduction 1015.2 Structural Motifs and Permeability of Cyclic Peptide Natural Products 1015.3 Conformations of Passively Permeable Bioactive Cyclic Peptide Natural Products 1035.4 Recently Discovered Bioactive Cyclic Peptide Natural Products 1085.5 Conclusions 125References 1256 Chemical Approaches to Macrocycle Libraries 133Ziqing Qian, Patrick G. Dougherty and Dehua Pei6.1 Introduction 1336.2 Challenges Associated with Macrocyclic One]Bead]One-Compound Libraries 1346.3 Deconvolution of Macrocyclic Libraries 1346.4 Peptide]Encoded Macrocyclic Libraries 1366.5 DNA] Encoded Macrocyclic Libraries 1426.6 Parallel Synthesis of Macrocyclic Libraries 1426.7 Diversity] Oriented Synthesis 1456.8 Perspective 1476.9 Conclusion 149References 1507 Biological and Hybrid Biological/Chemical Strategies in Diversity Generation of Peptidic Macrocycles 155Francesca Vitali and Rudi Fasan7.1 Introduction 1557.2 Cyclic Peptide Libraries on Phage Particles 1557.3 Macrocyclic Peptide Libraries via In Vitro Translation 1667.4 Emerging Strategies for the Combinatorial Synthesis of Hybrid Macrocycles In Vitro and in Cells 1717.5 Comparative Analysis of Technologies 1757.6 Conclusions 178References 1788 Macrocycles for Protein–Protein Interactions 185Eilidh Leitch and Ali Tavassoli8.1 Introduction 1858.2 Library Approaches to Macrocyclic PPI Inhibitors 1868.3 Structural Mimicry 1928.4 Multi] Cycles for PPIs 1978.5 The Future for Targeting PPIs with Macrocycles 197References 200Part III The Synthetic Toolbox for Macrocycles 2059 Synthetic Strategies for Macrocyclic Peptides 207Éric Biron, Simon Vezina]Dawod and François Bédard9.1 Introduction to Peptide Macrocyclization 2079.2 One Size Does Not Fit All: Factors to Consider During Synthesis Design 2099.3 Peptide Macrocyclization in Solution 2139.4 Peptide Macrocyclization on Solid Support 2209.5 Peptide Macrocyclization by Disulfide Bond Formation 2269.6 Conclusion 229References 23010 Ring]Closing Metathesis]Based Methods in Chemical Biology: Building a Natural Product Inspired Macrocyclic Toolbox to Tackle Protein–Protein Interactions 243Jagan Gaddam, Naveen Kumar Mallurwar, Saidulu Konda, Mahender Khatravath, Madhu Aeluri, Prasenjit Mitra and Prabhat Arya10.1 Introduction 24310.2 Protein– Protein Interactions: Challenges and Opportunities 24310.3 Natural Products as Modulators of Protein–Protein Interactions 24310.4 Introduction to Ring]Closing Metathesis 24410.5 Selected Examples of Synthetic Macrocyclic Probes Using RCM]Based Approaches 24610.6 Summary 259References 25911 The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition 265Ashok D. Pehere and Andrew D. Abell11.1 Introduction 26511.2 Dipolar Cycloaddition Reactions 26611.3 Macrocyclic Peptidomimetics 26711.4 Macrocyclic β]Strand Mimetics as Cysteine Protease Inhibitors 27311.5 Conclusion 275References 27712 Palladium]Catalyzed Synthesis of Macrocycles 281Thomas O. Ronson, William P. Unsworth and Ian J. S. Fairlamb12.1 Introduction 28112.2 Stille Reaction 28112.3 Suzuki– Miyaura Reaction 28512.4 Heck Reaction 28812.5 Sonogashira Reaction 29012.6 Tsuji– Trost Reaction 29312.7 Other Reactions 29512.8 Conclusion 298References 29813 Alternative Strategies for the Construction of Macrocycles 307Jeffrey Santandrea, Anne]Catherine Bédard, Mylène de Léséleuc, Michaël Raymond and Shawn K. Collins13.1 Introduction 30713.2 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation 30713.3 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation: Ring Expansion and Photochemical Methods 32013.4 Alternative Methods for Macrocyclization Involving Carbon–Oxygen Bond Formation 32213.5 Alternative Methods for Macrocyclization Involving Carbon–Nitrogen Bond Formation 32713.6 Alternative Methods for Macrocyclization Involving Carbon–Sulfur Bond Formation 32813.7 Conclusion and Summary 331References 33214 Macrocycles from Multicomponent Reactions 339Ludger A. Wessjohann, Ricardo A. W. Neves Filho, Alfredo R. Puentes and Micjel Chávez Morejón14.1 Introduction 33914.2 General Aspects of Multicomponent Reactions (MCRs) in Macrocycle Syntheses 34414.3 Concluding Remarks and Future Perspectives 369References 37115 Synthetic Approaches Used in the Scale]Up of Macrocyclic Clinical Candidates 377Jongrock Kong15.1 Introduction 37715.2 Background 37715.3 Literature Examples 37815.4 Conclusions 406References 406Part IV Macrocycles in Drug Development: Case Studies 41116 Overview of Macrocycles in Clinical Development and Clinically Used 413Silvia Stotani and Fabrizio Giordanetto16.1 Introduction 41316.2 Datasets Generation 41316.3 Marketed Macrocyclic Drugs 41416.4 Macrocycles in Clinical Studies 42216.5 De Novo Designed Macrocycles 42916.6 Overview and Conclusions 436Appendix 16.A 43716.A.1 Methods 437References 49017 The Discovery of Macrocyclic IAP Inhibitors for the Treatment of Cancer 501Nicholas K. Terrett17.1 Introduction 50117.2 DNA]Programmed Chemistry Macrocycle Libraries 50217.3 A New Macrocycle Ring Structure 50417.4 Design and Profiling of Bivalent Macrocycles 50617.5 Improving the Profile of the Bivalent Macrocycles 51017.6 Selection of the Optimal Bivalent Macrocyclic IAP Antagonist 51217.7 Summary 515Acknowledgments 515References 51618 Discovery and Pharmacokinetic–Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and c]Ros Oncogene 1 519Shinji Yamazaki, Justine L. Lam and Ted W. Johnson18.1 Introduction 51918.2 Discovery and Synthesis 52018.3 Evaluation of Pharmacokinetic Properties Including CNS Penetration 53118.4 Evaluation of Pharmacokinetic–Pharmacodynamic (PKPD) Profiles 53618.5 Conclusion 540References 54019 Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP]102 545Hamid R. Hoveyda, Graeme L. Fraser, Eric Marsault, René Gagnon and Mark L. Peterson19.1 Introduction 54519.2 Advanced AA3 and Tether SAR 54819.3 Structural Studies 55419.4 Conclusions 554Acknowledgments 555References 55620 Solithromycin: Fourth]Generation Macrolide Antibiotic 559David Pereira, Sara Wu, Shingai Majuru, Stephen E. Schneider and Lovy Pradeep20.1 Introduction 55920.2 Structure–Activity Relationship (SAR) of Ketolides and Selection of Solithromycin 55920.3 Mechanism of Action 56420.4 Overcoming the Ketek Effect 56820.5 Manufacture of Solithromycin 56920.6 Polymorphism 56920.7 Pharmaceutical Development 56920.8 Clinical Data 57420.9 Summary 574References 574Index 579