PRACTICAL MEDICINAL CHEMISTRY WITH MACROCYCLES: DESIGN, SYNTHESIS, AND CASE STUDIES

Part I Challenges Specific to Macrocycles 1
1 Contemporary Macrocyclization Technologies 3
2 A Practical Guide to Structural Aspects of Macrocycles (NMR, X ]Ray, and Modeling) 25
3 Designing Orally Bioavailable Peptide and Peptoid Macrocycles 59

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
5 Bioactive and Membrane ]Permeable Cyclic Peptide Natural Products 101
6 Chemical Approaches to Macrocycle Libraries 133
7 Biological and Hybrid Biological/Chemical Strategies in Diversity Generation of Peptidic Macrocycles 155
8 Macrocycles for Protein–Protein Interactions 185

Part III The Synthetic Toolbox for Macrocycles 205
9 Synthetic Strategies for Macrocyclic Peptides 207
10 Ring ]Closing Metathesis ]Based Methods in Chemical Biology: Building a Natural Product Inspired Macrocyclic Toolbox to Tackle Protein–Protein Interactions 243
11 The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition 265
12 Palladium ]Catalyzed Synthesis of Macrocycles 281
13 Alternative Strategies for the Construction of Macrocycles 307
14 Macrocycles from Multicomponent Reactions 339
15 Synthetic Approaches Used in the Scale ]Up of Macrocyclic Clinical Candidates 377

Part IV Macrocycles in Drug Development: Case Studies 411
16 Overview of Macrocycles in Clinical Development and Clinically Used 413
17 The Discovery of Macrocyclic IAP Inhibitors for the Treatment of Cancer 501
18 Discovery and Pharmacokinetic–Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and c ]Ros Oncogene 1 519
19 Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP ]102 545
20 Solithromycin: Fourth ]Generation Macrolide Antibiotic 559

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

Author Information
• Eric Marsault, PhD, is an Associate Professor of pharmacology at the University of Sherbrooke as well as the Director of the Quebec Network for Drug Discovery. Previously, he was 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 25 years of experience in the pharmaceutical industry.