Practical Medicinal Chemistry with Macrocycles

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]