Practical Medicinal Chemistry with Macrocycles

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

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 Protein–Protein 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 François Bédard 9.1 Introduction to Peptide Macrocyclization 207 9.2 One Size Does Not Fit All: Factors to Consider During Synthesis Design 209 9.3 Peptide Macrocyclization in Solution 213 9.4 Peptide Macrocyclization on Solid Support 220 9.5 Peptide Macrocyclization by Disulfide Bond Formation 226 9.6 Conclusion 229 References 230 10 Ring]Closing Metathesis]Based Methods in Chemical Biology: Building a Natural Product Inspired Macrocyclic Toolbox to Tackle Protein–Protein Interactions 243 Jagan Gaddam, Naveen Kumar Mallurwar, Saidulu Konda, Mahender Khatravath, Madhu Aeluri, Prasenjit Mitra and Prabhat Arya 10.1 Introduction 243 10.2 Protein– Protein Interactions: Challenges and Opportunities 243 10.3 Natural Products as Modulators of Protein–Protein Interactions 243 10.4 Introduction to Ring]Closing Metathesis 244 10.5 Selected Examples of Synthetic Macrocyclic Probes Using RCM]Based Approaches 246 10.6 Summary 259 References 259 11 The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition 265 Ashok D. Pehere and Andrew D. Abell 11.1 Introduction 265 11.2 Dipolar Cycloaddition Reactions 266 11.3 Macrocyclic Peptidomimetics 267 11.4 Macrocyclic β]Strand Mimetics as Cysteine Protease Inhibitors 273 11.5 Conclusion 275 References 277 12 Palladium]Catalyzed Synthesis of Macrocycles 281 Thomas O. Ronson, William P. Unsworth and Ian J. S. Fairlamb 12.1 Introduction 281 12.2 Stille Reaction 281 12.3 Suzuki– Miyaura Reaction 285 12.4 Heck Reaction 288 12.5 Sonogashira Reaction 290 12.6 Tsuji– Trost Reaction 293 12.7 Other Reactions 295 12.8 Conclusion 298 References 298 13 Alternative Strategies for the Construction of Macrocycles 307 Jeffrey Santandrea, Anne]Catherine Bédard, Mylène de Léséleuc, Michaël Raymond and Shawn K. Collins 13.1 Introduction 307 13.2 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation 307 13.3 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation: Ring Expansion and Photochemical Methods 320 13.4 Alternative Methods for Macrocyclization Involving Carbon–Oxygen Bond Formation 322 13.5 Alternative Methods for Macrocyclization Involving Carbon–Nitrogen Bond Formation 327 13.6 Alternative Methods for Macrocyclization Involving Carbon–Sulfur Bond Formation 328 13.7 Conclusion and Summary 331 References 332 14 Macrocycles from Multicomponent Reactions 339 Ludger A. Wessjohann, Ricardo A. W. Neves Filho, Alfredo R. Puentes and Micjel Chávez Morejón 14.1 Introduction 339 14.2 General Aspects of Multicomponent Reactions (MCRs) in Macrocycle Syntheses 344 14.3 Concluding Remarks and Future Perspectives 369 References 371 15 Synthetic Approaches Used in the Scale]Up of Macrocyclic Clinical Candidates 377 Jongrock Kong 15.1 Introduction 377 15.2 Background 377 15.3 Literature Examples 378 15.4 Conclusions 406 References 406 Part IV Macrocycles in Drug Development: Case Studies 411 16 Overview of Macrocycles in Clinical Development and Clinically Used 413 Silvia Stotani and Fabrizio Giordanetto 16.1 Introduction 413 16.2 Datasets Generation 413 16.3 Marketed Macrocyclic Drugs 414 16.4 Macrocycles in Clinical Studies 422 16.5 De Novo Designed Macrocycles 429 16.6 Overview and Conclusions 436 Appendix 16.A 437 16.A.1 Methods 437 References 490 17 The Discovery of Macrocyclic IAP Inhibitors for the Treatment of Cancer 501 Nicholas K. Terrett 17.1 Introduction 501 17.2 DNA]Programmed Chemistry Macrocycle Libraries 502 17.3 A New Macrocycle Ring Structure 504 17.4 Design and Profiling of Bivalent Macrocycles 506 17.5 Improving the Profile of the Bivalent Macrocycles 510 17.6 Selection of the Optimal Bivalent Macrocyclic IAP Antagonist 512 17.7 Summary 515 Acknowledgments 515 References 516 18 Discovery and Pharmacokinetic–Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and c]Ros Oncogene 1 519 Shinji Yamazaki, Justine L. Lam and Ted W. Johnson 18.1 Introduction 519 18.2 Discovery and Synthesis 520 18.3 Evaluation of Pharmacokinetic Properties Including CNS Penetration 531 18.4 Evaluation of Pharmacokinetic–Pharmacodynamic (PKPD) Profiles 536 18.5 Conclusion 540 References 540 19 Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP]102 545 Hamid R. Hoveyda, Graeme L. Fraser, Eric Marsault, René Gagnon and Mark L. Peterson 19.1 Introduction 545 19.2 Advanced AA3 and Tether SAR 548 19.3 Structural Studies 554 19.4 Conclusions 554 Acknowledgments 555 References 556 20 Solithromycin: Fourth]Generation Macrolide Antibiotic 559 David Pereira, Sara Wu, Shingai Majuru, Stephen E. Schneider and Lovy Pradeep 20.1 Introduction 559 20.2 Structure–Activity Relationship (SAR) of Ketolides and Selection of Solithromycin 559 20.3 Mechanism of Action 564 20.4 Overcoming the Ketek Effect 568 20.5 Manufacture of Solithromycin 569 20.6 Polymorphism 569 20.7 Pharmaceutical Development 569 20.8 Clinical Data 574 20.9 Summary 574 References 574 Index 579