Practical Medicinal Chemistry with Macrocycles: Design, Synthesis, and Case Studies

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 INDICE: Foreword xiii .Introduction xv .About the Contributors xix .Part I Challenges Specific to Macrocycles 1 .1 Contemporary Macrocyclization Technologies 3Serge 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) 25David 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 59David 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 79Ludger 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 101Andrew 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 133Ziqing 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 155Francesca 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 185Eilidh 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 207Éric 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 243Jagan 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 265Ashok D. Pehere and Andrew D. Abell .11.1 Introduction 265 .11.2 Dipolar Cycloaddition Reactions 266 .11.3 Macrocyclic Peptidomimetics 267 .11.4 Macrocyclic ]Strand Mimetics as Cysteine Protease Inhibitors 273 .11.5 Conclusion 275 .References 277 .12 Palladium ]Catalyzed Synthesis of Macrocycles 281Thomas 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 307Jeffrey 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 339Ludger 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 377Jongrock 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 413Silvia 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 501Nicholas 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 519Shinji 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 545Hamid 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 559David 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 . 

• ISBN: 978-1-119-09256-8
• Editorial: Wiley–Blackwell
• Encuadernacion: Cartoné
• Páginas: 624
• Fecha Publicación: 03/10/2017
• Nº Volúmenes: 1
• Idioma: Inglés