Practical Medicinal Chemistry with Macrocycles

Design, Synthesis, and Case Studies
 
 
Standards Information Network (Verlag)
  • erschienen am 3. August 2017
  • |
  • 624 Seiten
 
E-Book | PDF mit Adobe-DRM | Systemvoraussetzungen
978-1-119-09258-2 (ISBN)
 
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
1. Auflage
  • Englisch
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  • USA
John Wiley & Sons Inc
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  • 38,94 MB
978-1-119-09258-2 (9781119092582)
weitere Ausgaben werden ermittelt
Eric Marsault, PhD, is Professor of Pharmacology and Medicinal Chemistry at the University ofSherbrooke 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.
1 - Title Page [Seite 5]
2 - Copyright Page [Seite 6]
3 - Contents [Seite 7]
4 - Foreword [Seite 15]
5 - Introduction [Seite 17]
6 - About the Contributors [Seite 21]
7 - Part I Challenges Specific to Macrocycles [Seite 35]
7.1 - Chapter 1 Contemporary Macrocyclization Technologies [Seite 37]
7.1.1 - 1.1 Introduction [Seite 37]
7.1.2 - 1.2 Challenges Inherent to the Synthesis of Macrocycles [Seite 37]
7.1.3 - 1.3 Challenges in Macrocycle Characterization [Seite 40]
7.1.4 - 1.4 Macrocyclization Methods [Seite 42]
7.1.5 - 1.5 Cyclization on the Solid Phase [Seite 48]
7.1.6 - 1.6 Summary [Seite 51]
7.1.7 - References [Seite 52]
7.2 - Chapter 2 A Practical Guide to Structural Aspects of Macrocycles (NMR, X-Ray, and Modeling) [Seite 59]
7.2.1 - 2.1 Background [Seite 59]
7.2.1.1 - 2.1.1 Classes of Macrocycles Covered [Seite 59]
7.2.1.2 - 2.1.2 Applications of Macrocycles in Drug Design and Agriculture and the Role of Structural Information in These Applications [Seite 59]
7.2.1.3 - 2.1.3 Experimental Techniques (NMR and X-Ray) [Seite 64]
7.2.1.4 - 2.1.4 Modeling Studies [Seite 64]
7.2.2 - 2.2 Experimental Studies of Macrocycles [Seite 65]
7.2.2.1 - 2.2.1 NMR Experiments and Parameters That Yield Structural Information [Seite 65]
7.2.2.2 - 2.2.2 Protocols for 3D Structural Determination Using NMR [Seite 67]
7.2.2.3 - 2.2.3 Dynamic Aspects of Structures (NMR Relaxation) [Seite 69]
7.2.2.4 - 2.2.4 X-Ray Studies of Macrocycles [Seite 70]
7.2.2.5 - 2.2.5 Macrocycle-Receptor Interactions (NMR and X-Ray) [Seite 71]
7.2.3 - 2.3 Molecular Modeling of Macrocyclic Peptides [Seite 72]
7.2.3.1 - 2.3.1 Methods and Challenges in Modeling Cyclic Peptides [Seite 73]
7.2.3.1.1 - 2.3.1.1 Quantum Mechanics [Seite 73]
7.2.3.1.2 - 2.3.1.2 Molecular Mechanics [Seite 74]
7.2.3.2 - 2.3.2 Conformation, Dynamics, and Electrostatics of Cyclic Peptides [Seite 76]
7.2.3.2.1 - 2.3.2.1 NMR Spectroscopy Combined with MD Simulations [Seite 76]
7.2.3.2.2 - 2.3.2.2 Studying Large Conformational Ensembles and Folding [Seite 77]
7.2.3.2.3 - 2.3.2.3 Electrostatic Characteristics of Cyclic Peptides [Seite 77]
7.2.3.3 - 2.3.3 Modeling the Activity of Cyclic Peptides [Seite 78]
7.2.3.3.1 - 2.3.3.1 Cyclic Peptide Interactions with Molecular Targets [Seite 78]
7.2.3.3.2 - 2.3.3.2 Cyclic Peptide Nanotubes [Seite 79]
7.2.3.3.3 - 2.3.3.3 Membrane Permeation and Diffusion [Seite 80]
7.2.3.4 - 2.3.4 Engineering Cyclic Peptides as Grafting Scaffolds [Seite 80]
7.2.4 - 2.4 Summary [Seite 80]
7.2.5 - Acknowledgments [Seite 81]
7.2.6 - References [Seite 81]
7.3 - Chapter 3 Designing Orally Bioavailable Peptide and Peptoid Macrocycles [Seite 93]
7.3.1 - 3.1 Introduction [Seite 93]
7.3.2 - 3.2 Improving Peptide Plasma Half-Life [Seite 94]
7.3.3 - 3.3 Absorption, Bioavailability, and Methods for Predicting Absorption [Seite 95]
7.3.3.1 - 3.3.1 In Vitro Assays [Seite 95]
7.3.3.2 - 3.3.2 Paracellular Absorption [Seite 95]
7.3.3.3 - 3.3.3 Tight Junction Modifiers to Improve Paracellular Absorption [Seite 96]
7.3.3.4 - 3.3.4 Transcellular Absorption of Macrocycles [Seite 97]
7.3.3.4.1 - 3.3.4.1 Cyclization [Seite 97]
7.3.3.4.2 - 3.3.4.2 N-Methylation [Seite 99]
7.3.3.4.3 - 3.3.4.3 Cyclosporine A (CSA) [Seite 100]
7.3.3.4.4 - 3.3.4.4 Conformational Interconversion and H-Bond Networks [Seite 101]
7.3.3.4.5 - 3.3.4.5 Shielding [Seite 102]
7.3.3.4.6 - 3.3.4.6 Additional Strategies for Managing Hydrogen Bond Donors [Seite 103]
7.3.4 - 3.4 In Silico Modeling [Seite 104]
7.3.5 - 3.5 Future Directions [Seite 105]
7.3.6 - References [Seite 106]
8 - Part II Classes of Macrocycles and Their Potential for Drug Discovery [Seite 111]
8.1 - Chapter 4 Natural and Nature-Inspired Macrocycles: A Chemoinformatic Overview and Relevant Examples [Seite 113]
8.1.1 - 4.1 Introduction to Natural Macrocycles as Drugs and Drug Leads [Seite 113]
8.1.2 - 4.2 Biosynthetic Pathways, Natural Role, and Biotechnological Access [Seite 113]
8.1.3 - 4.3 QSAR and Chemoinformatic Analyses of Common Features [Seite 118]
8.1.4 - 4.4 Case Studies: Selected Natural Macrocycles of Special Relevance in Medicinal Chemistry [Seite 122]
8.1.5 - References [Seite 125]
8.2 - Chapter 5 Bioactive and Membrane-Permeable Cyclic Peptide Natural Products [Seite 135]
8.2.1 - 5.1 Introduction [Seite 135]
8.2.2 - 5.2 Structural Motifs and Permeability of Cyclic Peptide Natural Products [Seite 135]
8.2.3 - 5.3 Conformations of Passively Permeable Bioactive Cyclic Peptide Natural Products [Seite 137]
8.2.3.1 - 5.3.1 Flexible Scaffolds [Seite 137]
8.2.3.2 - 5.3.2 Structural Analogues [Seite 139]
8.2.3.3 - 5.3.3 Lipophilic (AlogP?>?3) Peptides and Reported Bioactivities [Seite 141]
8.2.4 - 5.4 Recently Discovered Bioactive Cyclic Peptide Natural Products [Seite 142]
8.2.4.1 - 5.4.1 Midsized Macrocycles [Seite 143]
8.2.4.1.1 - 5.4.1.1 Cytotoxics [Seite 143]
8.2.4.1.2 - 5.4.1.2 Antibacterials [Seite 148]
8.2.4.1.3 - 5.4.1.3 Antivirals [Seite 150]
8.2.4.1.4 - 5.4.1.4 Antiparasitics [Seite 150]
8.2.4.1.5 - 5.4.1.5 Antifungals [Seite 151]
8.2.4.1.6 - 5.4.1.6 Protease Inhibitors [Seite 151]
8.2.4.1.7 - 5.4.1.7 Other Bioactivities [Seite 152]
8.2.4.2 - 5.4.2 Large/Complex Peptides [Seite 154]
8.2.4.2.1 - 5.4.2.1 Cystine Knots [Seite 154]
8.2.4.2.2 - 5.4.2.2 Lantibiotics [Seite 158]
8.2.5 - 5.5 Conclusions [Seite 159]
8.2.6 - References [Seite 159]
8.3 - Chapter 6 Chemical Approaches to Macrocycle Libraries [Seite 167]
8.3.1 - 6.1 Introduction [Seite 167]
8.3.2 - 6.2 Challenges Associated with Macrocyclic One-Bead-One-Compound Libraries [Seite 168]
8.3.3 - 6.3 Deconvolution of Macrocyclic Libraries [Seite 168]
8.3.4 - 6.4 Peptide-Encoded Macrocyclic Libraries [Seite 170]
8.3.5 - 6.5 DNA-Encoded Macrocyclic Libraries [Seite 176]
8.3.6 - 6.6 Parallel Synthesis of Macrocyclic Libraries [Seite 176]
8.3.7 - 6.7 Diversity-Oriented Synthesis [Seite 179]
8.3.8 - 6.8 Perspective [Seite 181]
8.3.9 - 6.9 Conclusion [Seite 183]
8.3.10 - References [Seite 184]
8.4 - Chapter 7 Biological and Hybrid Biological/Chemical Strategies in Diversity Generation of Peptidic Macrocycles [Seite 189]
8.4.1 - 7.1 Introduction [Seite 189]
8.4.2 - 7.2 Cyclic Peptide Libraries on Phage Particles [Seite 189]
8.4.2.1 - 7.2.1 Disulfide-Bridged Cyclic Peptide Libraries [Seite 190]
8.4.2.2 - 7.2.2 From Phage Display to Peptide Macrocycle Design [Seite 194]
8.4.2.3 - 7.2.3 Bicyclic Peptide Libraries on Phage [Seite 196]
8.4.3 - 7.3 Macrocyclic Peptide Libraries via In Vitro Translation [Seite 200]
8.4.3.1 - 7.3.1 In Vitro Cyclic Peptide Libraries Via Chemical Cross-Linking [Seite 200]
8.4.3.2 - 7.3.2 In Vitro Macrocyclic Peptide Libraries Via the FIT and RaPID System [Seite 202]
8.4.4 - 7.4 Emerging Strategies for the Combinatorial Synthesis of Hybrid Macrocycles In Vitro and in Cells [Seite 205]
8.4.4.1 - 7.4.1 Macrocyclic Organo-Peptide Hybrids (MOrPHs) [Seite 205]
8.4.4.2 - 7.4.2 Synthesis of Macrocyclic Peptides in Living Cells [Seite 207]
8.4.5 - 7.5 Comparative Analysis of Technologies [Seite 209]
8.4.6 - 7.6 Conclusions [Seite 212]
8.4.7 - References [Seite 212]
8.5 - Chapter 8 Macrocycles for Protein-Protein Interactions [Seite 219]
8.5.1 - 8.1 Introduction [Seite 219]
8.5.2 - 8.2 Library Approaches to Macrocyclic PPI Inhibitors [Seite 220]
8.5.2.1 - 8.2.1 SICLOPPS [Seite 220]
8.5.2.2 - 8.2.2 FIT and RaPID [Seite 224]
8.5.3 - 8.3 Structural Mimicry [Seite 226]
8.5.3.1 - 8.3.1 ?-Strands [Seite 226]
8.5.3.2 - 8.3.2 ?-Helices [Seite 228]
8.5.4 - 8.4 Multi-Cycles for PPIs [Seite 231]
8.5.5 - 8.5 The Future for Targeting PPIs with Macrocycles [Seite 231]
8.5.6 - References [Seite 234]
9 - Part III The Synthetic Toolbox for Macrocycles [Seite 239]
9.1 - Chapter 9 Synthetic Strategies for Macrocyclic Peptides [Seite 241]
9.1.1 - 9.1 Introduction to Peptide Macrocyclization [Seite 241]
9.1.1.1 - 9.1.1 Cyclic Peptide Topologies [Seite 241]
9.1.1.2 - 9.1.2 Solution-Phase Versus Solid-Supported Macrocyclization [Seite 242]
9.1.2 - 9.2 One Size Does Not Fit All: Factors to Consider During Synthesis Design [Seite 243]
9.1.2.1 - 9.2.1 Ring Size [Seite 243]
9.1.2.2 - 9.2.2 Incorporation of Turn-Inducing Elements [Seite 243]
9.1.2.3 - 9.2.3 C-Terminal Epimerization [Seite 245]
9.1.2.4 - 9.2.4 Choosing the Right Macrocyclization Site [Seite 245]
9.1.3 - 9.3 Peptide Macrocyclization in Solution [Seite 247]
9.1.3.1 - 9.3.1 Ring Contraction Strategies [Seite 247]
9.1.3.2 - 9.3.2 Sulfur-Mediated Macrocyclizations [Seite 249]
9.1.3.3 - 9.3.3 Cyclic Depsipeptides and Peptoids [Seite 253]
9.1.4 - 9.4 Peptide Macrocyclization on Solid Support [Seite 254]
9.1.4.1 - 9.4.1 Side Chain Anchoring [Seite 255]
9.1.4.2 - 9.4.2 Backbone Amide Anchoring [Seite 256]
9.1.4.3 - 9.4.3 Safety-Catch Resin Anchoring and Cyclative Cleavage [Seite 259]
9.1.5 - 9.5 Peptide Macrocyclization by Disulfide Bond Formation [Seite 260]
9.1.5.1 - 9.5.1 Disulfide Bond Formation in Solution [Seite 260]
9.1.5.2 - 9.5.2 Disulfide Bond Formation on Solid Support [Seite 262]
9.1.6 - 9.6 Conclusion [Seite 263]
9.1.7 - References [Seite 264]
9.2 - Chapter 10 Ring-Closing Metathesis-Based Methods in Chemical Biology: Building a Natural Product-Inspired Macrocyclic Toolbox to Tackle Protein-Protein Interactions [Seite 277]
9.2.1 - 10.1 Introduction [Seite 277]
9.2.2 - 10.2 Protein-Protein Interactions: Challenges and Opportunities [Seite 277]
9.2.3 - 10.3 Natural Products as Modulators of Protein-Protein Interactions [Seite 277]
9.2.4 - 10.4 Introduction to Ring-Closing Metathesis [Seite 278]
9.2.4.1 - 10.4.1 Ring-Closing Olefin Metathesis [Seite 279]
9.2.4.2 - 10.4.2 Z-Selective Ring-Closing Metathesis [Seite 279]
9.2.5 - 10.5 Selected Examples of Synthetic Macrocyclic Probes Using RCM-Based Approaches [Seite 280]
9.2.5.1 - 10.5.1 Identification of Sonic Hedgehog Inhibitor from the RCM Library [Seite 280]
9.2.5.2 - 10.5.2 Identification of Antimalarial Compounds from the RCM Library [Seite 282]
9.2.5.3 - 10.5.3 Synthesis of Natural Product-Like Molecules Using RCM as the Key Strategy [Seite 283]
9.2.5.4 - 10.5.4 Alkaloid Natural Product-Inspired Macrocyclic Chemical Probes [Seite 283]
9.2.5.5 - 10.5.5 Indoline Alkaloid-Inspired Macrocyclic Chemical Probes [Seite 283]
9.2.5.6 - 10.5.6 Tetrahydroquinoline Alkaloid-Like Macrocyclic Chemical Probes [Seite 285]
9.2.5.7 - 10.5.7 Enantio-enriched Benzofuran-Based Macrocyclic Toolbox [Seite 286]
9.2.5.8 - 10.5.8 Building a Diverse 14-Membered Ring-Based Chemical Toolbox [Seite 287]
9.2.5.9 - 10.5.9 Building a Diverse C-Linked Glyco-Based Macrocyclic Toolbox [Seite 290]
9.2.5.10 - 10.5.10 Evaluation of the Chemical Toolbox in Search for Anti-angiogenesis Agents [Seite 290]
9.2.6 - 10.6 Summary [Seite 293]
9.2.7 - References [Seite 293]
9.3 - Chapter 11 The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition [Seite 299]
9.3.1 - 11.1 Introduction [Seite 299]
9.3.2 - 11.2 Dipolar Cycloaddition Reactions [Seite 300]
9.3.3 - 11.3 Macrocyclic Peptidomimetics [Seite 301]
9.3.3.1 - 11.3.1 Macrocyclic Antagonists for the Treatment of Cancer [Seite 301]
9.3.3.2 - 11.3.2 Dimeric Macrocyclic Antagonists of Apoptosis Proteins [Seite 302]
9.3.3.3 - 11.3.3 Macrocyclic Grb2 SH2 Domain Inhibitor [Seite 302]
9.3.3.4 - 11.3.4 STAT3 Inhibitors [Seite 303]
9.3.3.5 - 11.3.5 Histone Deacetylase Inhibitors [Seite 303]
9.3.3.6 - 11.3.6 Somatostatin Modulators [Seite 307]
9.3.4 - 11.4 Macrocyclic ?-Strand Mimetics as Cysteine Protease Inhibitors [Seite 307]
9.3.5 - 11.5 Conclusion [Seite 309]
9.3.6 - References [Seite 311]
9.4 - Chapter 12 Palladium-Catalyzed Synthesis of Macrocycles [Seite 315]
9.4.1 - 12.1 Introduction [Seite 315]
9.4.2 - 12.2 Stille Reaction [Seite 315]
9.4.3 - 12.3 Suzuki-Miyaura Reaction [Seite 319]
9.4.4 - 12.4 Heck Reaction [Seite 322]
9.4.5 - 12.5 Sonogashira Reaction [Seite 324]
9.4.6 - 12.6 Tsuji-Trost Reaction [Seite 327]
9.4.7 - 12.7 Other Reactions [Seite 329]
9.4.8 - 12.8 Conclusion [Seite 332]
9.4.9 - References [Seite 332]
9.5 - Chapter 13 Alternative Strategies for the Construction of Macrocycles [Seite 341]
9.5.1 - 13.1 Introduction [Seite 341]
9.5.2 - 13.2 Alternative Methods for Macrocyclization Involving Carbon-Carbon Bond Formation [Seite 341]
9.5.2.1 - 13.2.1 Alkylation [Seite 341]
9.5.2.2 - 13.2.2 Glaser-Hay Coupling [Seite 343]
9.5.2.3 - 13.2.3 Nickel/Ruthenium/ Copper-Catalyzed Couplings [Seite 345]
9.5.2.4 - 13.2.4 Wittig and Other Olefinations [Seite 349]
9.5.2.5 - 13.2.5 Cyclopropanation [Seite 350]
9.5.2.6 - 13.2.6 Oxidative Coupling of Arenes [Seite 351]
9.5.2.7 - 13.2.7 Gold Catalysis [Seite 353]
9.5.3 - 13.3 Alternative Methods for Macrocyclization Involving Carbon-Carbon Bond Formation: Ring Expansion and Photochemical Methods [Seite 354]
9.5.3.1 - 13.3.1 Ring Expansion [Seite 354]
9.5.3.2 - 13.3.2 Photochemical Methods [Seite 356]
9.5.4 - 13.4 Alternative Methods for Macrocyclization Involving Carbon-Oxygen Bond Formation [Seite 356]
9.5.4.1 - 13.4.1 Chan-Lam-Evans Coupling [Seite 356]
9.5.4.2 - 13.4.2 Alkylation [Seite 357]
9.5.4.3 - 13.4.3 Nucleophilic Aromatic Substitution [Seite 358]
9.5.4.4 - 13.4.4 Ullmann Coupling [Seite 359]
9.5.4.5 - 13.4.5 C-H Activation [Seite 360]
9.5.5 - 13.5 Alternative Methods for Macrocyclization Involving Carbon-Nitrogen Bond Formation [Seite 361]
9.5.5.1 - 13.5.1 Alkylation [Seite 361]
9.5.5.2 - 13.5.2 Nucleophilic Aromatic Substitution [Seite 361]
9.5.5.3 - 13.5.3 Ullmann Coupling [Seite 362]
9.5.6 - 13.6 Alternative Methods for Macrocyclization Involving Carbon-Sulfur Bond Formation [Seite 362]
9.5.6.1 - 13.6.1 Ramberg-Bäcklund Reaction [Seite 363]
9.5.6.2 - 13.6.2 Thiol-Ene Reaction [Seite 363]
9.5.7 - 13.7 Conclusion and Summary [Seite 365]
9.5.8 - References [Seite 366]
9.6 - Chapter 14 Macrocycles from Multicomponent Reactions [Seite 373]
9.6.1 - 14.1 Introduction [Seite 373]
9.6.2 - 14.2 General Aspects of Multicomponent Reactions (MCRs) in Macrocycle Syntheses [Seite 378]
9.6.2.1 - 14.2.1 The MiB Concept [Seite 378]
9.6.2.2 - 14.2.2 Unidirectional Multicomponent Macrocyclizations/Cyclooligomerizations [Seite 379]
9.6.2.3 - 14.2.3 Bidirectional Multicomponent Macrocyclizations [Seite 394]
9.6.2.4 - 14.2.4 Iterative IMCR-Based Macrocyclizations with Multiple Bifunctional Building Blocks [Seite 403]
9.6.3 - 14.3 Concluding Remarks and Future Perspectives [Seite 403]
9.6.4 - References [Seite 405]
9.7 - Chapter 15 Synthetic Approaches Used in the Scale-Up of Macrocyclic Clinical Candidates [Seite 411]
9.7.1 - 15.1 Introduction [Seite 411]
9.7.2 - 15.2 Background [Seite 411]
9.7.3 - 15.3 Literature Examples [Seite 412]
9.7.3.1 - 15.3.1 Macrolactonization [Seite 412]
9.7.3.2 - 15.3.2 Macrolactamization [Seite 412]
9.7.3.3 - 15.3.3 Ring-Closing Metathesis [Seite 418]
9.7.3.4 - 15.3.4 Metal-Catalyzed Cross-Coupling [Seite 429]
9.7.3.5 - 15.3.5 Oxidative Disulfide Formation [Seite 433]
9.7.3.6 - 15.3.6 Other Approaches [Seite 438]
9.7.4 - 15.4 Conclusions [Seite 440]
9.7.5 - References [Seite 440]
10 - Part IV Macrocycles in Drug Development: Case Studies [Seite 445]
10.1 - Chapter 16 Overview of Macrocycles in Clinical Development and Clinically Used [Seite 447]
10.1.1 - 16.1 Introduction [Seite 447]
10.1.2 - 16.2 Datasets Generation [Seite 447]
10.1.3 - 16.3 Marketed Macrocyclic Drugs [Seite 448]
10.1.3.1 - 16.3.1 General Characteristics [Seite 448]
10.1.3.2 - 16.3.2 Cyclic Peptides [Seite 448]
10.1.3.3 - 16.3.3 Macrolides and Ansamycins [Seite 450]
10.1.3.4 - 16.3.4 Bioavailability and Doses of Macrocyclic Drugs [Seite 453]
10.1.4 - 16.4 Macrocycles in Clinical Studies [Seite 456]
10.1.4.1 - 16.4.1 General Characteristics [Seite 456]
10.1.4.2 - 16.4.2 Cyclic Peptides [Seite 456]
10.1.4.3 - 16.4.3 Macrolides and Ansamycins [Seite 460]
10.1.5 - 16.5 De Novo Designed Macrocycles [Seite 463]
10.1.5.1 - 16.5.1 Protease and Polymerase Inhibitors [Seite 463]
10.1.5.2 - 16.5.2 Kinase Inhibitors [Seite 468]
10.1.6 - 16.6 Overview and Conclusions [Seite 470]
10.1.7 - Appendix 16.A [Seite 471]
10.1.7.1 - 16.A.1 Methods [Seite 471]
10.1.8 - References [Seite 524]
10.2 - Chapter 17 The Discovery of Macrocyclic IAP Inhibitors for the Treatment of Cancer [Seite 535]
10.2.1 - 17.1 Introduction [Seite 535]
10.2.2 - 17.2 DNA-Programmed Chemistry Macrocycle Libraries [Seite 536]
10.2.2.1 - 17.2.1 Initial IAP Screening Macrocycle Hits [Seite 536]
10.2.2.2 - 17.2.2 A Follow-Up DPC Macrocycle Library [Seite 537]
10.2.3 - 17.3 A New Macrocycle Ring Structure [Seite 538]
10.2.3.1 - 17.3.1 Functional Caspase?3 Rescue Assay [Seite 540]
10.2.4 - 17.4 Design and Profiling of Bivalent Macrocycles [Seite 540]
10.2.4.1 - 17.4.1 In Vitro Antiproliferative Activity [Seite 540]
10.2.4.2 - 17.4.2 Pharmacokinetic Profiling [Seite 543]
10.2.4.3 - 17.4.3 In Vivo Efficacy in a Xenograft Model [Seite 543]
10.2.5 - 17.5 Improving the Profile of the Bivalent Macrocycles [Seite 544]
10.2.5.1 - 17.5.1 Replacing Carboxylic Acids [Seite 545]
10.2.5.2 - 17.5.2 Replacing Triazole Linkers [Seite 546]
10.2.6 - 17.6 Selection of the Optimal Bivalent Macrocyclic IAP Antagonist [Seite 546]
10.2.6.1 - 17.6.1 Synthesis of the Optimal Bivalent Macrocycle [Seite 547]
10.2.6.2 - 17.6.2 In Vitro Profiling [Seite 548]
10.2.6.3 - 17.6.3 Pharmacokinetic Profiling [Seite 549]
10.2.6.4 - 17.6.4 In Vivo Efficacy in a Xenograft Model [Seite 549]
10.2.7 - 17.7 Summary [Seite 549]
10.2.8 - Acknowledgments [Seite 549]
10.2.9 - References [Seite 550]
10.3 - Chapter 18 Discovery and Pharmacokinetic-Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and c-Ros Oncogene 1 [Seite 553]
10.3.1 - 18.1 Introduction [Seite 553]
10.3.2 - 18.2 Discovery and Synthesis [Seite 554]
10.3.2.1 - 18.2.1 Background-Macrocyclic Kinase Inhibitors [Seite 554]
10.3.2.2 - 18.2.2 Crizotinib Discovery and SAR [Seite 554]
10.3.2.3 - 18.2.3 Resistance Mechanisms to Crizotinib [Seite 554]
10.3.2.4 - 18.2.4 Program Goals and Lab Objectives [Seite 555]
10.3.2.5 - 18.2.5 Structural Data, Potency, ADME-Crizotinib and PF-06439015 [Seite 555]
10.3.2.6 - 18.2.6 Acyclic ALK Inhibitors [Seite 556]
10.3.2.7 - 18.2.7 Design from Acyclic Structural Data [Seite 556]
10.3.2.8 - 18.2.8 Macrocyclic ALK Inhibitors [Seite 558]
10.3.2.9 - 18.2.9 Selectivity Strategy [Seite 560]
10.3.2.10 - 18.2.10 Structural Analysis of PF?06463922 (4q) [Seite 564]
10.3.2.11 - 18.2.11 Overlapping Potency and Selectivity [Seite 564]
10.3.2.12 - 18.2.12 Synthesis of PF?06463922 (4q) [Seite 564]
10.3.2.13 - 18.2.13 Summary of Discovery and Synthesis [Seite 565]
10.3.3 - 18.3 Evaluation of Pharmacokinetic Properties Including CNS Penetration [Seite 565]
10.3.3.1 - 18.3.1 Background [Seite 565]
10.3.3.2 - 18.3.2 Lab Objectives and In Vitro Screening for CNS Penetration [Seite 566]
10.3.3.3 - 18.3.3 ADME Evaluation [Seite 566]
10.3.3.4 - 18.3.4 In Vivo Assessment of Brain Penetration in Rats Measuring Brain Homogenate and CSF [Seite 566]
10.3.3.5 - 18.3.5 In Vivo Assessment of Brain Penetration in Rats Using Quantitative Autoradiography [Seite 567]
10.3.3.6 - 18.3.6 In Vivo Assessment of Spatial Brain Distribution in Mice Using Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-MS) [Seite 567]
10.3.3.7 - 18.3.7 In Vivo Efficacy Assessment of Orthotopic Brain Tumor Model Using Magnetic Resonance Imaging [Seite 568]
10.3.3.8 - 18.3.8 PK and Brain Penetration Summary [Seite 570]
10.3.4 - 18.4 Evaluation of Pharmacokinetic-Pharmacodynamic (PKPD) Profiles [Seite 570]
10.3.4.1 - 18.4.1 Background [Seite 570]
10.3.4.2 - 18.4.2 In Vivo Nonclinical Studies [Seite 570]
10.3.4.3 - 18.4.3 PK Modeling [Seite 571]
10.3.4.4 - 18.4.4 PKPD Modeling for Target Modulation [Seite 571]
10.3.4.5 - 18.4.5 PKDZ Modeling for Antitumor Efficacy [Seite 571]
10.3.4.6 - 18.4.6 Quantitative Comparison of Exposure-Response Relationships [Seite 572]
10.3.4.7 - 18.4.7 PKPD Summary [Seite 572]
10.3.5 - 18.5 Conclusion [Seite 574]
10.3.6 - References [Seite 574]
10.4 - Chapter 19 Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP-102 [Seite 579]
10.4.1 - 19.1 Introduction [Seite 579]
10.4.2 - 19.2 Advanced AA3 and Tether SAR [Seite 582]
10.4.2.1 - 19.2.1 AA3 Options for Improved CYP3A4 Profile [Seite 582]
10.4.2.2 - 19.2.2 Additional Tether SAR Explorations: Reduction of the Aromatic Content and Additional Conformational Constraints through Methyl Substitution [Seite 585]
10.4.3 - 19.3 Structural Studies [Seite 588]
10.4.4 - 19.4 Conclusions [Seite 588]
10.4.5 - Acknowledgments [Seite 589]
10.4.6 - References [Seite 590]
10.5 - Chapter 20 Solithromycin: Fourth-Generation Macrolide Antibiotic [Seite 593]
10.5.1 - 20.1 Introduction [Seite 593]
10.5.2 - 20.2 Structure-Activity Relationship (SAR) of Ketolides and Selection of Solithromycin [Seite 593]
10.5.2.1 - 20.2.1 MIC Testing of Triazole Analogues [Seite 593]
10.5.2.2 - 20.2.2 Importance of 2?Fluorine for Activity [Seite 593]
10.5.2.3 - 20.2.3 In Vitro Genotoxicity Studies on Solithromycin [Seite 594]
10.5.2.4 - 20.2.4 Mouse PK and Protection Studies [Seite 595]
10.5.3 - 20.3 Mechanism of Action [Seite 598]
10.5.3.1 - 20.3.1 Ribosome Binding of Antibiotics [Seite 598]
10.5.3.2 - 20.3.2 Ribosome Binding of Solithromycin [Seite 599]
10.5.3.3 - 20.3.3 Solithromycin Protein Inhibition [Seite 601]
10.5.4 - 20.4 Overcoming the Ketek Effect [Seite 602]
10.5.5 - 20.5 Manufacture of Solithromycin [Seite 603]
10.5.6 - 20.6 Polymorphism [Seite 603]
10.5.7 - 20.7 Pharmaceutical Development [Seite 603]
10.5.7.1 - 20.7.1 Capsule Development [Seite 605]
10.5.7.1.1 - 20.7.1.1 Capsule Formulation Development [Seite 605]
10.5.7.1.2 - 20.7.1.2 Capsule Manufacturing Process [Seite 606]
10.5.7.1.3 - 20.7.1.3 Capsule Dissolution [Seite 606]
10.5.7.2 - 20.7.2 Powder for Oral Suspension [Seite 606]
10.5.7.3 - 20.7.3 Solithromycin for Injection [Seite 607]
10.5.7.3.1 - 20.7.3.1 The Challenge of Solithromycin IV Formulation Development [Seite 607]
10.5.8 - 20.8 Clinical Data [Seite 608]
10.5.8.1 - 20.8.1 Phase 1 PK and Bioavailability [Seite 608]
10.5.8.2 - 20.8.2 Phases 2 and 3 Trials [Seite 608]
10.5.9 - 20.9 Summary [Seite 608]
10.5.10 - References [Seite 608]
11 - Index [Seite 613]
12 - Supplemental Images [Seite 620]
13 - EULA [Seite 652]

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