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 (ongoing, H. Kessler - due Jan 2017)IntroductionAbout the contributorsPart I Challenges Specific to Macrocycles1. Contemporary Macrocyclization TechnologiesSerge Zaretsky and Andrei K. Yudin1.1. Introduction1.2. Challenges inherent to the synthesis of macrocycles1.3. Challenges in macrocycle characterization1.4. Macrocyclization methods1.5. Cyclization on the solid phase1.6. Summary1.7. References2. A Practical Guide to Structural Aspects of Macrocycles (NMR, X-Ray and Modelling)David J. Craik, Quentin Kaas and Conan K. WangAbstract2.1. Background2.1.1. Classes of macrocycles covered2.1.2. Applications of macromolecules in drug design and agriculture and the role of structural information in these applications2.1.3. Experimental techniques (NMR and X-ray)2.1.4. Modelling studies2.2. Experimental studies of macrocycles2.2.1. NMR experiments and parameters that yield structural information2.2.2. Protocols for 3D structural determination using NMR2.2.3. Dynamic aspects of structures (NMR relaxation)2.2.4. X-ray studies of macrocycles2.2.5. Macrocycle-receptor interactions (both NMR and X-ray)2.3. Molecular modelling of macrocyclic peptides2.3.1. Methods and challenges in modelling cyclic peptides2.3.1.1. Quantum mechanics2.3.1.2. Molecular mechanics2.3.2. Conformation, dynamics and electrostatics of cyclic peptides2.3.2.1. NMR spectroscopy combined with MD simulations2.3.2.2. Studying large conformational ensembles and folding2.3.2.3. Electrostatic characteristics of cyclic peptides2.3.3. Modelling the activity of cyclic peptides2.3.3.1. Cyclic peptide interactions with molecular targets2.3.3.2. Cyclic peptide nanotubes2.3.3.3. Membrane permeation and diffusion2.3.4. Engineering cyclic peptides as grafting scaffolds2.4. Summary2.5. Acknowledgments2.6. List of abbreviations2.7. References3. Designing Orally Bioavailable Peptide and Peptoid MacrocyclesDavid Price, Alan M. Mathiowetz and Spiros Liras3.1. Introduction3.2. Improving peptide plasma half-life3.3. Absorption, bioavailability and methods for predicting absorption3.3.1. In vitro assays3.3.2. Paracellular absorption3.3.3. Tight junction modifiers to improve paracellular absorption3.3.4. Transcellular absorption of macrocycles3.3.4.1. Cyclisation3.3.4.2. N-methylation3.3.4.3. Cyclosporine A3.3.4.4. Conformational interconversion and H-bond networks3.3.4.5. Shielding3.3.4.6. Additional strategies for managing H-bond networks3.4. In silico modeling3.5. Future directions3.6. ReferencesPart II Classes of Macrocycles and their Potential for Drug Discovery4. Natural and Nature-Inspired Macrocycles - A Chemoinformatic Overview and Relevant ExamplesLudger A. Wessjohann, Richard Bartelt, Ricardo A. W. Neves FilhoWolfgang Brandt4.1. Introduction to natural macrocycles as drugs and drug leads4.2. Biosynthetic pathways, natural role and biotechnological access4.3. QSAR and chemoinformatic analyses of common features4.4. Case studies: selected natural macrocycles of special relevance in medicinal chemistry4.5. References5. Bioactive and Membrane-Permeable Cyclic Peptide Natural ProductsAndrew T. Bockus and R. Scott Lokey5.1. Introduction5.2. Structural motifs and permeability of cyclic peptide natural products5.3. Conformations of passively permeable bioactive cyclic peptide natural products5.3.1. Flexible scaffolds5.3.2. Structural analogs5.3.3. Lipophilic (AlogP > 3) peptides and reported bioactivities5.4. Recently discovered bioactive cyclic peptide natural products5.4.1. Mid-Sized Macrocycles5.4.1.1. Cytotoxics5.4.1.2. Antibacterials5.4.1.3. Antivirals5.4.1.4. Antiparasitics5.4.1.5. Antifungals5.4.1.6. Protease Inhibitors5.4.1.7. Other Bioactivities5.4.2. Large/Complex Peptides5.4.2.1. Cystine knots5.4.2.2. Lantibiotics5.5. Conclusions5.6. References6. Chemical Approaches to Macrocycle LibrariesZiqing Qian, Patrick G. Douherty, Dehua Pei6.1. Introduction6.2. Challenges Associated with Macrocyclic OBOC Libraries6.3. Deconvolution of Macrocyclic Libraries6.4. Peptide-Encoded Macrocyclic Libraries6.5. DNA-Encoded Macrocyclic Libraries6.6. Parallel Synthesis of Macrocyclic Libraries6.7. Diversity-Oriented Synthesis6.8. Perspective6.9. Conclusion6.10. References7. Biological and Hybrid Biological/Chemical Strategies in Diversity Generation of Peptidic MacrocyclesFrancesca Vitali & Rudi Fasan7.1. Introduction7.2. Cyclic peptide libraries on phage particles7.2.1. Disulfide-bridged cyclic peptide libraries7.2.2. From phage display to peptide macrocycle design7.2.3. Bicyclic peptide libraries on phage7.3. Macrocyclic peptide libraries via in vitro translation7.3.1. In vitro cyclic peptide libraries via chemical crosslinking7.3.2. In vitro macrocyclic peptide libraries via the FIT and RaPID system7.4. Emerging strategies for the combinatorial synthesis of hybrid macrocycles in vitro and in cells.7.4.1. Macrocyclic Organo-Peptide Hybrids (MOrPHs).7.4.2. Synthesis of macrocyclic peptides in living cells.7.5. Comparative analysis of technologies7.6. Conclusion7.7. References8. Macrocycles for Protein-Protein InteractionsEilidh Leitch & Ali Tavassoli8.1. Introduction8.2. Library Approaches to Macrocyclic PPI Inhibitors8.2.1. SICLOPPS8.2.2. FIT and RaPID8.3. Structural Mimicry8.3.1. ß-strands8.3.2. alpha-helices8.4. Multi-cycles for PPIs8.5. The Future for Targeting PPIs with Macrocycles8.6. List of Abbreviations8.7. ReferencesPart III The Synthetic Toolbox for Macrocycles9. Synthetic Strategies for Macrocyclic PeptidesÉric Biron, Simon Vézina-Dawood, François Bédard9.1. Introduction: peptide macrocyclization9.1.1. Cyclic peptide topologies9.1.2. Solution phase vs solid-supported macrocyclizations9.2. One size does not fit all: factors to consider during synthesis design9.2.1. Ring size9.2.2. Incorporation of turn-inducing elements9.2.3. C-terminus epimerization9.2.4. Choosing the right macrocyclization site9.3. Peptide macrocyclization in solution9.3.1. Ring contraction strategies9.3.2. Sulfur-mediated macrocyclizations9.3.3. Cyclic depsipeptides and peptoids9.4. Peptide Macrocyclization on solid support9.4.1. Side chain anchoring9.4.2. Backbone amide anchoring9.4.3. Safety-catch anchoring and cyclative cleavage9.5. Peptide Macrocyclization by disulfide bond formation9.5.1. Disulfide bond formation in solution9.5.2. Disulfide bond formation on solid support9.6. Conclusion10. Ring Closing Metathesis-Based Methods in Chemical Biology: Building a Natural Product-Inspired Macrocyclic Toolbox to Tackle Protein-Protein InteractionsJagan Gaddam, Naveen Kumar Mallurwar, Saidulu Konda, Mahender Khatravath, MadhuAeluri, Prasenjit Mitra and Prabhat Arya10.1. Introduction10.2. Protein-Protein Interactions - Challenges and Opportunities10.3. Natural Products as Modulators of Protein-Protein Interactions10.4. Introduction to Ring Closing Metathesis (RCM)10.4.1. Ring Closing Olefin Metathesis10.4.2. Z-Selective Ring Closing Metathesis10.5. Selected Examples of Synthetic Macrocyclic Probes using RCM Based Approaches10.5.1. Identification of Sonic Hedgehog Inhibitor from the RCM Library10.5.2. Identification of Anti-Malarial Compounds from the RCM Library10.5.3. Synthesis of Natural Product-Like Molecules Using RCM as the Key Strate10.5.4. Alkaloid Natural Product-Inspired Macrocyclic Chemical Probes10.5.5. Indoline Alkaloid-Inspired Macrocyclic Chemical Probes10.5.6. Tetrahydroquinoline Alkaloid-like Macrocyclic Chemical Probes10.5.7. Enantio-enriched, Benzofuran-based, Macrocyclic Toolbox10.5.8. Building a Diverse 14-Membered Ring-based Chemical Toolbox10.5.9. Building a Diverse C-Linked Glyco-based Macrocyclic Toolbox10.5.10. Evaluation of the chemical toolbox to search for anti-angiogenesis agents10.6. Summary10.7. References11. The Synthesis of Macrocycles by Huisgen CycloadditionAshok D. Pehere and Andrew D. Abell11.1. Introduction11.2. Dipolar cycloaddition reactions11.3. Macrocyclic peptidomimetics11.3.1. Macrocyclic antagonists for the treatment of cancer11.3.2. Dimeric macrocyclic antagonists of apoptosis proteins11.3.3. Macrocyclic Grb2 SH2 domain inhibitors11.3.4. STAT3 inhibitors11.3.5. Histone deacetylase inhibitors11.3.6. Somatostatin modulators11.4. Macrocyclic?n?Ò-strand mimetics as protease inhibitors11.5. Conclusion11.6. References12. Palladium-catalysed synthesis of macrocyclesThomas O. Ronson, William P. Unsworth and Ian J. S. Fairlamb12.1. Introduction12.2. Stille Reaction12.3. Suzuki-Miyaura reaction12.4. Heck reaction12.5. Sonogashira reaction12.6. Tsuji-Trost reaction12.7. Other reactions12.8. Conclusion12.9. References13. Alternative Strategies for the Construction of MacrocyclesJeffrey Santandrea, Anne-Catherine Bédard, Mylène de Léséleuc, Michael Raymond and Shawn K. Collins13.1. Introduction13.2. Alternative methods for macrocyclization involving Carbon-Carbon bond formation13.2.1. Alkylation13.2.2. Glaser-Hay coupling13.2.3. Nickel /Ruthenium/Copper-catalyzed couplings13.2.4. Wittig and other olefinations13.2.5. Cyclopropanation13.2.6. Oxidative coupling of arenes13.2.7. Gold catalysis13.3. Alternative methods for macrocyclization involving carbon-carbon bond formation: ring expansion and photochemical methods13.3.1. Ring expansion13.3.2. Photochemical methods13.4. Alternative methods for macrocyclization involving carbon-oxygen bond formation.13.4.1. Cham-Lam-Evans coupling13.4.2. Alkylation13.4.3. Nucleophilic aromatic substitution13.4.4. Ullmann coupling13.4.5. C-H activation13.5. Alternative methods for macrocyclization involving carbon-nitrogen bond formation.13.5.1. Alkylation13.5.2. Nucleophilic aromatic substitution13.5.3. Ullmann coupling13.6. Alternative methods for macrocyclization involving carbon-sulfur bond formation.13.6.1. Ramberg-Bäcklund chemistry13.6.2. Thiol-ene reaction13.7. Conclusion and summary13.8. References14. Macrocycles from Multicomponent ReactionsLudger A. Wessjohann, Ricardo A. W. Neves Filho, Alfredo R. Puentes, Micjel C. Morejon14.1. Introduction14.2. General Aspects of Multicomponent Reactions (MCRs) in Macrocycle Syntheses14.2.1. The MiB Concept14.2.2. Unidirectional Multicomponent Macrocyclizations / Cyclooligomerizations14.2.3. Bidirectional Multicomponent Macrocyclizations14.2.4. Iterative IMCR-based macrocyclizations with multiple bifunctional building blocks14.3. Concluding remarks and future perspectives14.4. References15. Synthetic Approaches Used in the Scale-up of Macrocyclic Clinical CandidatesJonrock Kong15.1. Introduction15.2. Background15.3. Literature Examples15.3.1. Macrolactonization15.3.2. Macrolactamization15.3.3. Ring-closing Metathesis (RCM)15.3.4. Metal-Catalyzed Cross-Coupling15.3.5. Oxidative Disulfide Formation15.3.6. Other Approaches15.4. Conclusions15.5. ReferencesPart IV Macrocycles in Drug Development - Case Studies16. Overview of Macrocycles in Clinical Development and Clinically UsedSilvia Stotani and Fabrizio Giordanetto16.1. Introduction16.2. Datasets generation16.3. Marketed macrocyclic drugs16.3.1. General characteristics16.3.2. Cyclic peptides16.3.3. Macrolides and ansamycins16.3.4. Bioavailability and doses of macrocyclic drugs16.4. Macrocycles in clinical studies16.4.1. General characteristics16.4.2. Cyclic peptides16.4.3. Macrolides and ansamycins16.5. De novo designed macrocycles16.5.1. Protease and polymerase inhibitors16.5.2. Kinase inhibitors16.6. Overview and conclusions16.7. List of abbreviations16.8. References17. The Discovery of Macrocyclic IAP Inhibitors for the Treatment of CancerNicholas K. Terrett17.1. Introduction17.2. DNA-programmed chemistry macrocycle libraries17.2.1. Initial IAP screening macrocycle hits17.2.2. A follow-up DPC macrocycle library17.3. A new macrocycle ring structure17.3.1. Functional caspase-3 rescue assay17.4. Design and profiling of bivalent macrocycles17.4.1. In vitro anti-proliferative activity17.4.2. Pharmacokinetic profiling17.4.3. In vivo efficacy in a xenograft model17.5. Improving the profile of bivalent macrocycles17.5.1. Replacing carboxylic acids17.5.2. Replacing triazole linkers17.6. Selection of the optimal bivalent macrocyclic IAP antagonist17.6.1. Synthesis of the optimal bivalent macrocycle17.6.2. In vitro profiling17.6.3. Pharmacokinetic profiling17.6.4. In vivo efficacy in a xenograft model17.7. Summary17.8. References18. Discovery and Pharmacokinetic-Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and cRos Oncogene 1Shinji Yamazaki, Justine L. Lam, Ted W. Johnson18.1. Introduction18.2. Discovery and Synthesis18.2.1. Background - Macrocyclic kinase inhibitors18.2.2. Crizotinib Discovery and SAR18.2.3. Resistance Mechanisms to Crizotinib18.2.4. Program Goals and Lab Objectives18.2.5. Crizotinib and PF-06439015 - structural data, potency, ADME18.2.6. Acyclic ALK inhibitors18.2.7. Design from Acyclic Structural Data18.2.8. Macrocyclic ALK inhibitors18.2.9. Selectivity Strategy18.2.10. Structural Analysis of PF 0646392218.2.11. Overlapping potency and selectivity18.2.12. Synthesis of PF 0646392218.2.13. Summary of Discovery and Synthesis18.3. Evaluation of Pharmacokinetic Properties including CNS Penetration18.3.1. Background18.3.2. Lab Objectives and In Vitro Screening for CNS Penetration18.3.3. ADME Evaluation18.3.4. In Vivo Assessment of Brain Penetration in Rats Measuring Brain Homogenate and CSF18.3.5. In Vivo Assessment of Brain Penetration in Rats using Quantitative Autoradiography18.3.6. In Vivo Assessment of Spatial Brain Distribution in Mice using Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry Imaging18.3.7. In Vivo Efficacy Assessment of Orthotopic Brain Tumor Model using Magnetic Resonance Imaging18.3.8. PK and Brain Penetration Summary18.4. Evaluation of Pharmacokinetic-Pharmacodynamic (PKPD) Profiles18.4.1. Background18.4.2. In Vivo Nonclinical Studies18.4.3. PK Modelling18.4.4. PKPD Modelling for Target Modulation18.4.5. PKDZ Modelling for Antitumor Efficacy18.4.6. Quantitative Comparison of Exposure-Response Relationships18.4.7. PKPD Summary18.5. Conclusion18.6. List of Abbreviations18.7. References19. Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP-102Hamid R. Hoveyda, Graeme L. Fraser, Eric Marsault, René Gagnon and Mark L. Peterson19.1. Introduction19.2. Advanced AA3 and tether SAR19.2.1. AA3 options for improved CYP3A4 profile19.2.2. Additional Tether SAR Explorations: Reduction of the Aromatic Content and Additional Conformational Constraints through Methyl Substitution.19.3. Structural studies19.4. Conclusions19.5. References20. Solithromycin: Fourth Generation Macrolide AntibioticDavid Pereira, Sara Wu, Shingai Majuru, Stephen E. Schneider and Lovy Pradeep20.1. Introduction20.2. Structure-activity relationship of ketolides and selection of solithromycin20.2.1. MIC testing of triazole analogs20.2.2. Importance of 2-fluorine for activity20.2.3. In vitro genotoxicity studies on solithromycin20.2.4. Mouse PK and protection studies20.3. Mechanism of action20.3.1. Ribosome binding of antibiotics20.3.2. Ribosome binding of solithromycin20.3.3. Solithromycin protein inhibition20.4. Overcoming the Ketek effect20.5. Manufacture of solithromycin20.6. Polymorphism20.7. Pharmaceutical development20.7.1. Capsule development20.7.1.1. Capsule formulation development20.7.1.2. Capsule manufacturing process20.7.1.3. Capsule dissolution20.7.2. Powder for oral suspension20.7.3. Solithromycin for injection20.7.3.1. The challenge of solithromycin i.v. formulation development20.8. Clinical data20.8.1. Phase 1 PK and bioavailability20.8.2. Phases 2 and 3 trials20.9. SummaryIndex