{"product_id":"practical-medicinal-chemistry-with-macrocycles-isbn-9781119092568","title":"Practical Medicinal Chemistry with Macrocycles","description":"\u003cp\u003eIncluding 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.\u003c\/p\u003e \u003cul\u003e \u003cli\u003eProvides needed background to build a program in macrocycle drug discovery –design criteria, macrocycle profiles, applications, and limitations\u003c\/li\u003e \u003cli\u003eFeatures chapters contributed from leading international figures involved in macrocyclic drug discovery efforts\u003c\/li\u003e \u003cli\u003eCovers design criteria, typical profile of current macrocycles, applications, and limitations\u003c\/li\u003e \u003c\/ul\u003e \u003cp\u003eForeword xiii\u003c\/p\u003e \u003cp\u003eIntroduction xv\u003c\/p\u003e \u003cp\u003eAbout the Contributors xix\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart I Challenges Specific to Macrocycles 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e1 Contemporary Macrocyclization Technologies 3\u003cbr\u003e\u003ci\u003eSerge Zaretsky and Andrei K. Yudin\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Introduction 3\u003c\/p\u003e \u003cp\u003e1.2 Challenges Inherent to the Synthesis of Macrocycles 3\u003c\/p\u003e \u003cp\u003e1.3 Challenges in Macrocycle Characterization 6\u003c\/p\u003e \u003cp\u003e1.4 Macrocyclization Methods 8\u003c\/p\u003e \u003cp\u003e1.5 Cyclization on the Solid Phase 14\u003c\/p\u003e \u003cp\u003e1.6 Summary 17\u003c\/p\u003e \u003cp\u003eReferences 18\u003c\/p\u003e \u003cp\u003e2 A Practical Guide to Structural Aspects of Macrocycles (NMR, X]Ray, and Modeling) 25\u003cbr\u003e\u003ci\u003eDavid J. Craik, Quentin Kaas and Conan K. Wang\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Background 25\u003c\/p\u003e \u003cp\u003e2.2 Experimental Studies of Macrocycles 31\u003c\/p\u003e \u003cp\u003e2.3 Molecular Modeling of Macrocyclic Peptides 38\u003c\/p\u003e \u003cp\u003e2.4 Summary 46\u003c\/p\u003e \u003cp\u003eAcknowledgments 47\u003c\/p\u003e \u003cp\u003eReferences 47\u003c\/p\u003e \u003cp\u003e3 Designing Orally Bioavailable Peptide and Peptoid Macrocycles 59\u003cbr\u003e\u003ci\u003eDavid A. Price, Alan M. Mathiowetz and Spiros Liras\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction 59\u003c\/p\u003e \u003cp\u003e3.2 Improving Peptide Plasma Half]Life 60\u003c\/p\u003e \u003cp\u003e3.3 Absorption, Bioavailability, and Methods for Predicting Absorption 61\u003c\/p\u003e \u003cp\u003e3.4 In Silico Modeling 70\u003c\/p\u003e \u003cp\u003e3.5 Future Directions 71\u003c\/p\u003e \u003cp\u003eReferences 72\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart II Classes of Macrocycles and Their Potential for Drug Discovery 77\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e4 Natural and Nature]Inspired Macrocycles: A Chemoinformatic Overview and Relevant Examples 79\u003cbr\u003e\u003ci\u003eLudger A. Wessjohann, Richard Bartelt and Wolfgang Brandt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction to Natural Macrocycles as Drugs and Drug Leads 79\u003c\/p\u003e \u003cp\u003e4.2 Biosynthetic  Pathways, Natural Role, and Biotechnological Access 79\u003c\/p\u003e \u003cp\u003e4.3 QSAR and Chemoinformatic Analyses of Common Features 84\u003c\/p\u003e \u003cp\u003e4.4 Case Studies: Selected Natural Macrocycles of Special Relevance in Medicinal Chemistry 88\u003c\/p\u003e \u003cp\u003eReferences 91\u003c\/p\u003e \u003cp\u003e5 Bioactive and Membrane]Permeable Cyclic Peptide Natural Products 101\u003cbr\u003e\u003ci\u003eAndrew T. Bockus and R. Scott Lokey\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 101\u003c\/p\u003e \u003cp\u003e5.2 Structural Motifs and Permeability of Cyclic Peptide Natural Products 101\u003c\/p\u003e \u003cp\u003e5.3 Conformations of Passively Permeable Bioactive Cyclic Peptide Natural Products 103\u003c\/p\u003e \u003cp\u003e5.4 Recently Discovered Bioactive Cyclic Peptide Natural Products 108\u003c\/p\u003e \u003cp\u003e5.5 Conclusions 125\u003c\/p\u003e \u003cp\u003eReferences 125\u003c\/p\u003e \u003cp\u003e6 Chemical Approaches to Macrocycle Libraries 133\u003cbr\u003e\u003ci\u003eZiqing Qian, Patrick G. Dougherty and Dehua Pei\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 133\u003c\/p\u003e \u003cp\u003e6.2 Challenges Associated with Macrocyclic One]Bead]One-Compound Libraries 134\u003c\/p\u003e \u003cp\u003e6.3 Deconvolution of Macrocyclic Libraries 134\u003c\/p\u003e \u003cp\u003e6.4 Peptide]Encoded Macrocyclic Libraries 136\u003c\/p\u003e \u003cp\u003e6.5 DNA] Encoded Macrocyclic Libraries 142\u003c\/p\u003e \u003cp\u003e6.6 Parallel Synthesis of Macrocyclic Libraries 142\u003c\/p\u003e \u003cp\u003e6.7 Diversity] Oriented Synthesis 145\u003c\/p\u003e \u003cp\u003e6.8 Perspective 147\u003c\/p\u003e \u003cp\u003e6.9 Conclusion 149\u003c\/p\u003e \u003cp\u003eReferences 150\u003c\/p\u003e \u003cp\u003e7 Biological and Hybrid Biological\/Chemical Strategies in Diversity Generation of Peptidic Macrocycles 155\u003cbr\u003e\u003ci\u003eFrancesca Vitali and Rudi Fasan\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 155\u003c\/p\u003e \u003cp\u003e7.2 Cyclic Peptide Libraries on Phage Particles 155\u003c\/p\u003e \u003cp\u003e7.3 Macrocyclic Peptide Libraries via In Vitro Translation 166\u003c\/p\u003e \u003cp\u003e7.4 Emerging Strategies for the Combinatorial Synthesis of Hybrid Macrocycles In Vitro and in Cells 171\u003c\/p\u003e \u003cp\u003e7.5 Comparative Analysis of Technologies 175\u003c\/p\u003e \u003cp\u003e7.6 Conclusions 178\u003c\/p\u003e \u003cp\u003eReferences 178\u003c\/p\u003e \u003cp\u003e8 Macrocycles for Protein–Protein Interactions 185\u003cbr\u003e\u003ci\u003eEilidh Leitch and Ali Tavassoli\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 185\u003c\/p\u003e \u003cp\u003e8.2 Library Approaches to Macrocyclic PPI Inhibitors 186\u003c\/p\u003e \u003cp\u003e8.3 Structural Mimicry 192\u003c\/p\u003e \u003cp\u003e8.4 Multi] Cycles for PPIs 197\u003c\/p\u003e \u003cp\u003e8.5 The Future for Targeting PPIs with Macrocycles 197\u003c\/p\u003e \u003cp\u003eReferences 200\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart III The Synthetic Toolbox for Macrocycles 205\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e9 Synthetic Strategies for Macrocyclic Peptides 207\u003cbr\u003e\u003ci\u003eÉ\u003c\/i\u003e\u003ci\u003eric Biron, Simon Vezina\u003c\/i\u003e\u003ci\u003e]\u003c\/i\u003e\u003ci\u003eDawod and Fran\u003c\/i\u003e\u003ci\u003eç\u003c\/i\u003e\u003ci\u003eois B\u003c\/i\u003e\u003ci\u003eé\u003c\/i\u003e\u003ci\u003edard\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction to Peptide Macrocyclization 207\u003c\/p\u003e \u003cp\u003e9.2 One Size Does Not Fit All: Factors to Consider During Synthesis Design 209\u003c\/p\u003e \u003cp\u003e9.3 Peptide Macrocyclization in Solution 213\u003c\/p\u003e \u003cp\u003e9.4 Peptide Macrocyclization on Solid Support 220\u003c\/p\u003e \u003cp\u003e9.5 Peptide Macrocyclization by Disulfide Bond Formation 226\u003c\/p\u003e \u003cp\u003e9.6 Conclusion 229\u003c\/p\u003e \u003cp\u003eReferences 230\u003c\/p\u003e \u003cp\u003e10 Ring]Closing Metathesis]Based Methods in Chemical Biology: Building a Natural Product Inspired Macrocyclic Toolbox to Tackle Protein–Protein Interactions 243\u003cbr\u003e\u003ci\u003eJagan Gaddam, Naveen Kumar Mallurwar, Saidulu Konda, Mahender Khatravath, Madhu Aeluri, Prasenjit Mitra and Prabhat Arya\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 243\u003c\/p\u003e \u003cp\u003e10.2 Protein– Protein Interactions: Challenges and Opportunities 243\u003c\/p\u003e \u003cp\u003e10.3 Natural Products as Modulators of Protein–Protein Interactions 243\u003c\/p\u003e \u003cp\u003e10.4 Introduction to Ring]Closing Metathesis 244\u003c\/p\u003e \u003cp\u003e10.5 Selected Examples of Synthetic Macrocyclic Probes Using RCM]Based Approaches 246\u003c\/p\u003e \u003cp\u003e10.6 Summary 259\u003c\/p\u003e \u003cp\u003eReferences 259\u003c\/p\u003e \u003cp\u003e11 The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition 265\u003cbr\u003e\u003ci\u003eAshok D. Pehere and Andrew D. Abell\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 265\u003c\/p\u003e \u003cp\u003e11.2 Dipolar Cycloaddition Reactions 266\u003c\/p\u003e \u003cp\u003e11.3 Macrocyclic Peptidomimetics 267\u003c\/p\u003e \u003cp\u003e11.4 Macrocyclic β]Strand Mimetics as Cysteine Protease Inhibitors 273\u003c\/p\u003e \u003cp\u003e11.5 Conclusion 275\u003c\/p\u003e \u003cp\u003eReferences 277\u003c\/p\u003e \u003cp\u003e12 Palladium]Catalyzed Synthesis of Macrocycles 281\u003cbr\u003e\u003ci\u003eThomas O. Ronson, William P. Unsworth and Ian J. S. Fairlamb\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 281\u003c\/p\u003e \u003cp\u003e12.2 Stille Reaction 281\u003c\/p\u003e \u003cp\u003e12.3 Suzuki– Miyaura Reaction 285\u003c\/p\u003e \u003cp\u003e12.4 Heck Reaction 288\u003c\/p\u003e \u003cp\u003e12.5 Sonogashira Reaction 290\u003c\/p\u003e \u003cp\u003e12.6 Tsuji– Trost Reaction 293\u003c\/p\u003e \u003cp\u003e12.7 Other Reactions 295\u003c\/p\u003e \u003cp\u003e12.8 Conclusion 298\u003c\/p\u003e \u003cp\u003eReferences 298\u003c\/p\u003e \u003cp\u003e13 Alternative Strategies for the Construction of Macrocycles 307\u003cbr\u003e\u003ci\u003eJeffrey Santandrea, Anne\u003c\/i\u003e\u003ci\u003e]\u003c\/i\u003e\u003ci\u003eCatherine B\u003c\/i\u003e\u003ci\u003eé\u003c\/i\u003e\u003ci\u003edard, Myl\u003c\/i\u003e\u003ci\u003eè\u003c\/i\u003e\u003ci\u003ene de L\u003c\/i\u003e\u003ci\u003eé\u003c\/i\u003e\u003ci\u003es\u003c\/i\u003e\u003ci\u003eé\u003c\/i\u003e\u003ci\u003eleuc, Micha\u003c\/i\u003e\u003ci\u003eë\u003c\/i\u003e\u003ci\u003el Raymond and Shawn K. Collins\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 307\u003c\/p\u003e \u003cp\u003e13.2 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation 307\u003c\/p\u003e \u003cp\u003e13.3 Alternative Methods for Macrocyclization Involving Carbon–Carbon Bond Formation: Ring Expansion and Photochemical Methods 320\u003c\/p\u003e \u003cp\u003e13.4 Alternative Methods for Macrocyclization Involving Carbon–Oxygen Bond Formation 322\u003c\/p\u003e \u003cp\u003e13.5 Alternative Methods for Macrocyclization Involving Carbon–Nitrogen Bond Formation 327\u003c\/p\u003e \u003cp\u003e13.6 Alternative Methods for Macrocyclization Involving Carbon–Sulfur Bond Formation 328\u003c\/p\u003e \u003cp\u003e13.7 Conclusion and Summary 331\u003c\/p\u003e \u003cp\u003eReferences 332\u003c\/p\u003e \u003cp\u003e14 Macrocycles from Multicomponent Reactions 339\u003cbr\u003e\u003ci\u003eLudger A. Wessjohann, Ricardo A. W. Neves Filho, Alfredo R. Puentes and Micjel Ch\u003c\/i\u003e\u003ci\u003eá\u003c\/i\u003e\u003ci\u003evez Morej\u003c\/i\u003e\u003ci\u003eó\u003c\/i\u003e\u003ci\u003en\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 339\u003c\/p\u003e \u003cp\u003e14.2 General Aspects of Multicomponent Reactions (MCRs) in Macrocycle Syntheses 344\u003c\/p\u003e \u003cp\u003e14.3 Concluding Remarks and Future Perspectives 369\u003c\/p\u003e \u003cp\u003eReferences 371\u003c\/p\u003e \u003cp\u003e15 Synthetic Approaches Used in the Scale]Up of Macrocyclic Clinical Candidates 377\u003cbr\u003e\u003ci\u003eJongrock Kong\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 377\u003c\/p\u003e \u003cp\u003e15.2 Background 377\u003c\/p\u003e \u003cp\u003e15.3 Literature Examples 378\u003c\/p\u003e \u003cp\u003e15.4 Conclusions 406\u003c\/p\u003e \u003cp\u003eReferences 406\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart IV Macrocycles in Drug Development: Case Studies 411\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e16 Overview of Macrocycles in Clinical Development and Clinically Used 413\u003cbr\u003e\u003ci\u003eSilvia Stotani and Fabrizio Giordanetto\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 413\u003c\/p\u003e \u003cp\u003e16.2 Datasets Generation 413\u003c\/p\u003e \u003cp\u003e16.3 Marketed Macrocyclic Drugs 414\u003c\/p\u003e \u003cp\u003e16.4 Macrocycles in Clinical Studies 422\u003c\/p\u003e \u003cp\u003e16.5 De Novo Designed Macrocycles 429\u003c\/p\u003e \u003cp\u003e16.6 Overview and Conclusions 436\u003c\/p\u003e \u003cp\u003eAppendix 16.A 437\u003c\/p\u003e \u003cp\u003e16.A.1 Methods 437\u003c\/p\u003e \u003cp\u003eReferences 490\u003c\/p\u003e \u003cp\u003e17 The Discovery of Macrocyclic IAP Inhibitors for the Treatment of Cancer 501\u003cbr\u003e\u003ci\u003eNicholas K. Terrett\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 501\u003c\/p\u003e \u003cp\u003e17.2 DNA]Programmed Chemistry Macrocycle Libraries 502\u003c\/p\u003e \u003cp\u003e17.3 A New Macrocycle Ring Structure 504\u003c\/p\u003e \u003cp\u003e17.4 Design and Profiling of Bivalent Macrocycles 506\u003c\/p\u003e \u003cp\u003e17.5 Improving the Profile of the Bivalent Macrocycles 510\u003c\/p\u003e \u003cp\u003e17.6 Selection of the Optimal Bivalent Macrocyclic IAP Antagonist 512\u003c\/p\u003e \u003cp\u003e17.7 Summary 515\u003c\/p\u003e \u003cp\u003eAcknowledgments 515\u003c\/p\u003e \u003cp\u003eReferences 516\u003c\/p\u003e \u003cp\u003e18 Discovery and Pharmacokinetic–Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and c]Ros Oncogene 1 519\u003cbr\u003e\u003ci\u003eShinji Yamazaki, Justine L. Lam and Ted W. Johnson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 519\u003c\/p\u003e \u003cp\u003e18.2 Discovery and Synthesis 520\u003c\/p\u003e \u003cp\u003e18.3 Evaluation of Pharmacokinetic Properties Including CNS Penetration 531\u003c\/p\u003e \u003cp\u003e18.4 Evaluation of Pharmacokinetic–Pharmacodynamic (PKPD) Profiles 536\u003c\/p\u003e \u003cp\u003e18.5 Conclusion 540\u003c\/p\u003e \u003cp\u003eReferences 540\u003c\/p\u003e \u003cp\u003e19 Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP]102 545\u003cbr\u003e\u003ci\u003eHamid R. Hoveyda, Graeme L. Fraser, Eric Marsault, Ren\u003c\/i\u003e\u003ci\u003eé\u003c\/i\u003e\u003ci\u003e Gagnon and Mark L. Peterson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 545\u003c\/p\u003e \u003cp\u003e19.2 Advanced AA3 and Tether SAR 548\u003c\/p\u003e \u003cp\u003e19.3 Structural Studies 554\u003c\/p\u003e \u003cp\u003e19.4 Conclusions 554\u003c\/p\u003e \u003cp\u003eAcknowledgments 555\u003c\/p\u003e \u003cp\u003eReferences 556\u003c\/p\u003e \u003cp\u003e20 Solithromycin: Fourth]Generation Macrolide Antibiotic 559\u003cbr\u003e\u003ci\u003eDavid Pereira, Sara Wu, Shingai Majuru, Stephen E. Schneider and Lovy Pradeep\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 559\u003c\/p\u003e \u003cp\u003e20.2 Structure–Activity Relationship (SAR) of Ketolides and Selection of Solithromycin 559\u003c\/p\u003e \u003cp\u003e20.3 Mechanism of Action 564\u003c\/p\u003e \u003cp\u003e20.4 Overcoming the Ketek Effect 568\u003c\/p\u003e \u003cp\u003e20.5 Manufacture of Solithromycin 569\u003c\/p\u003e \u003cp\u003e20.6 Polymorphism 569\u003c\/p\u003e \u003cp\u003e20.7 Pharmaceutical Development 569\u003c\/p\u003e \u003cp\u003e20.8 Clinical Data 574\u003c\/p\u003e \u003cp\u003e20.9 Summary 574\u003c\/p\u003e \u003cp\u003eReferences 574\u003c\/p\u003e \u003cp\u003eIndex 579\u003c\/p\u003e \u003cp\u003e \u003c\/p\u003e   \u003cp\u003e \u003cstrong\u003eEric Marsault, PhD,\u003c\/strong\u003e 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.  \u003c\/p\u003e\u003cp\u003e \u003cstrong\u003eMark L. Peterson, PhD,\u003c\/strong\u003e 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.      \u003c\/p\u003e\u003cp\u003e Macrocycles are medium to large ring compounds that offer medicinal chemists the benefits of both small molecules and biomolecules – oral bioavailability and extended surface areas, respectively;  as a result, they possess great potential for modulation of difficult therapeutic targets. Accordingly, there is now extensive interest in the use of macrocycles for drug discovery, hence the need for a handy guidebook about the basics and practices of working with such compounds.   \u003c\/p\u003e\u003cp\u003e \u003cem\u003ePractical Medicinal Chemistry with Macrocycles\u003c\/em\u003e offers a practical resource for those scientists developing new therapeutic agents. With chapters contributed from leading international figures involved in macrocyclic drug discovery efforts, the book is broken into four parts: challenges  specific to macrocycles, classes of macrocycles and their potential in drug discovery, the synthetic toolbox for macrocycles, and case studies of macrocyclic marketed drugs and clinical candidates.   \u003c\/p\u003e\u003cp\u003e These aspects of the book combine to offer a number of key features that include:   \u003c\/p\u003e\u003cul\u003e \u003cli\u003eBackground to build a drug discovery program based on macrocycles – design criteria, molecular profiles, applications, potential pitfalls and limitations\u003c\/li\u003e \u003cli\u003eNumerous synthetic approaches and strategies to build, diversify and optimize macrocycles  in the context of medicinal chemistry efforts\u003c\/li\u003e \u003cli\u003eA wealth of successful examples and case studies to help deal with the synthetic and conceptual challenges of working with macrocycles\u003c\/li\u003e \u003c\/ul\u003e \u003cbr\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989833859301,"sku":"NP9781119092568","price":241.95,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9781119092568.jpg?v=1761785618","url":"https:\/\/k12savings.com\/products\/practical-medicinal-chemistry-with-macrocycles-isbn-9781119092568","provider":"K12savings","version":"1.0","type":"link"}