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 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