Contents

Macrocycles in Drug Discovery: Introduction xxi

Chapter 1 Bioactive Macrocycles from Nature 1David J. Newman and Gordon M. Cragg

1.1 Introduction 11.2 Macrolides and Peptide-based Bioactive

Compounds 31.2.1 Non-Ansamycin Antibiotics (Anti-infective

and Anti-tumor) 31.3 Ansamycins (Antimycobacterial and Antibacterial) 7

1.3.1 Rifamycins 71.3.2 Anthracimycin 81.3.3 Ansamitocins (Tubulin Interactive Agents) 81.3.4 Rhizoxin 101.3.5 Geldanamycin and Analogues/Hsp90

Inhibitors 101.4 Bryostatins (Protein Kinase C Inhibitors) 121.5 Epothilones 141.6 Rapamycins and ‘‘Rapalogs’’ 151.7 Peptidic Macrocycles 18

1.7.1 Gramicidin S (Antibiotic) 191.7.2 Ziconotide (Cone Snail Toxin) 191.7.3 Patellamides (Cytotoxic Cyclic Peptides) 211.7.4 Cyclic Histone Deacetylase Inhibitors

(HDACs) 211.8 Buruli Toxins (Mycolactones A/B; Necrotic

Contact Agents) 241.9 Eribulin (Halavens, E7389) 26

RSC Drug Discovery Series No. 40Macrocycles in Drug DiscoveryEdited by Jeremy Levinr The Royal Society of Chemistry 2015Published by the Royal Society of Chemistry, www.rsc.org

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1.10 Conclusion 26References 28

Chapter 2 Recent Advances in Macrocyclic Hsp90 Inhibitors 37D. M. Ramsey, R. R. A. Kitson, J. I. Levin, C. J. Moody andS. R. MCAlpine

2.1 Introduction 372.1.1 Macrocycles as Anticancer Agents 382.1.2 Heat Shock Protein 90 (Hsp90) as an

Oncogenic Target 402.2 Class I: Ansamycins and Derivatives 42

2.2.1 Geldanamycin 422.2.2 Geldanamycin Derivatives 452.2.3 Modifications to C19 482.2.4 Combination Therapies 50

2.3 Class II: Radicicol and Radanamycin 502.3.1 Direct Analogues of Radicicol 512.3.2 Radamide, Radester and Radanamycin 532.3.3 Radicicol-inspired Pyrazoles and Oxazoles 53

2.4 Class III: Macrocyclic o-Aminobenzamidesand Aminopyrimidines 54

2.5 Class IV: N-Middle Domain Hsp90 MacrocyclicInhibitors 592.5.1 SM122 vs. SM145 in Pull-down and

Biochemical Assays 632.5.2 SM122 vs. SM145 in Cell-based Assays 64

2.6 Conclusion 68References 68

Chapter 3 Epothilones 78Raphael Schiess and Karl-Heinz Altmann

3.1 Introduction 783.2 Epothilone B 803.3 Epothilone Analogs in Clinical Development and

Related Structures 813.3.1 Side Chain-Modified Analogs 813.3.2 Epoxide Modifications 873.3.3 9,10-Dehydroepothilones 923.3.4 Ixabepilone 95

3.4 Structural Studies and PharmacophoreModeling 97

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3.5 Conclusions 100References 100

Chapter 4 Macrocyclic Inhibitors of Zinc-dependent HistoneDeacetylases (HDACs) 109A. Ganesan

4.1 Genetics Versus Epigenetics 1094.2 Zinc-dependent Histone Deacetylases 1104.3 The Cyclic Tetrapeptide Natural Products with a

Ketone Warhead 1164.4 The Depsipeptide Natural Products with a Thiol

Warhead 1244.5 The Azumamide Natural Products with a

Carboxylic Acid Warhead 1304.6 Synthetic Macrocyclic HDAC Inhibitors 1324.7 Summary 1354.8 Notes 136References 136

Chapter 5 Designed Macrocyclic Kinase Inhibitors 141Anders Poulsen, Anthony D. William andBrian W. Dymock

5.1 Introduction 1415.1.1 Introduction to Macrocyclic Kinase

Inhibitors 1415.1.2 Literature Survey of Macrocyclic Kinase

Inhibitors 1425.2 Biology Rationale 155

5.2.1 Janus Kinases (JAKs) 1555.2.2 FMS-like Tyrosine Kinase 3 (FLT3) 1575.2.3 Cyclin-dependent Kinases (CDKs) 1575.2.4 Other Kinases 158

5.3 Medicinal Chemistry 1595.3.1 Macrocycle Design 1595.3.2 SAR and Structural Biology 1605.3.3 In Vitro Biology 1745.3.4 Physical Properties and In Vitro ADME 1755.3.5 Animal Models and Preclinical DMPK 1765.3.6 Summary of Preclinical Development 180

5.4 Synthesis 1815.4.1 Synthesis of SB1518 (Pacritinib, 1) 1815.4.2 Synthesis of SB1317 (3, TG02) 1845.4.3 Synthesis of SB1578 (2) 185

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5.5 Clinical Trials 1875.5.1 Overview 1875.5.2 Pacritinib Clinical Trials 1875.5.3 TG02 (SB1317, 3) Clinical Trials 195

5.6 Conclusion 198References 199

Chapter 6 Anti-Inflammatory Macrolides to Manage ChronicNeutrophilic Inflammation 206Michael Burnet, Jan-Hinrich Guse, Hans-Jurgen Gutke,Loic Guillot, Stefan Laufer, Ulrike Hahn, Michael P. Seed,Enriqueta Vallejo, Mary Eggers, Doug McKenzie,Wolfgang Albrecht and Michael J. Parnham

6.1 Introduction 2066.2 Efforts Toward the Discovery of Anti-Inflammatory

Macrolides 2076.3 Issues in Development of Anti-Inflammatory

Macrolides 2086.4 Is the Anti-Inflammatory Activity of Macrolides

Related to their Effects on Normal Flora orColonisation by Pathogens? 209

6.5 General Properties of Macrolides 2126.6 Reducing Antibacterial Effects of 14- and

15-Membered Macrolactone Macrolides 2136.7 Appropriate Doses for Anti-Inflammatory

Effects 2156.8 NAM Mode of Action – Multiple Effects with a

Common Element, or a Fortunate Collection ofMutually Supportive Actions? 216

6.9 Molecular Mechanisms of Macrolide Modulation ofInflammation 216

6.10 Pulmonary Disease, Azithromycin, andUnderlying Polarisation of ImmuneResponses 218

6.11 The ‘‘M17’’ Macrophages/Dendritic State 2216.12 Macrophage Polarization 2226.13 T Cell Polarisation 2236.14 Dendritic Cells 2246.15 Conjugated Anti-Inflammatory Macrolides 2246.16 Conclusion 230References 230

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Chapter 7 Linear and Macrocyclic Hepatitis C Virus ProteaseInhibitors: Inhibitor Design and MacrocyclizationStrategies for HCV Protease and Related Targets 235Wieslaw M. Kazmierski, Richard L. Jarvest, Jacob J. Plattnerand Xianfeng Li

7.1 Introduction 2357.2 Hepatitis C Virus and Current Treatment Options 2367.3 HCV Protease Inhibitors: Structural and Design

Considerations 2387.4 Clinical HCV Protease Inhibitors 246

7.4.1 Danoprevir (ITMN-191) 2477.4.2 Simeprevir (TMC435) 2477.4.3 GS-9256 2487.4.4 Vaniprevir (MK-7009) 2487.4.5 MK-5172 2487.4.6 MK-1220 2497.4.7 Faldaprevir (BI 201335) 2497.4.8 Asunaprevir (BMS-650032) 2507.4.9 GS-9451 250

7.4.10 ABT-450 and ACH-1625 2507.5 GSK and Anacor HCV Protease Inhibitor Discovery

Efforts 2517.5.1 Design of HCV PIs Incorporating Cyclic

Boronate (CB) and Benzoxaborole (BXB)Moieties 251

7.5.2 Macrocyclic Non-boron HCV PIs 2617.6 Selected Examples of Inhibitor Macrocyclization for

Related Targets 2677.6.1 HCV NS5B Polymerase Inhibitors 2697.6.2 Non-HCV Protease Inhibitors 269

7.7 Conclusion 271Acknowledgments 272References 273

Chapter 8 Macrocyclic Inhibitors of GPCR’s, Integrins andProtein–Protein Interactions 283Philipp Ermert, Kerstin Moehle and Daniel Obrecht

8.1 Macrocycles Are Privileged Structures in DrugDiscovery 283

8.2 Classes of Macrocycles 2848.2.1 Cyclic Peptides and Depsipeptides; Cyclic

Peptide Mimetics 284

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8.2.2 Protein Epitope Mimetics (PEM) 2858.2.3 Non Peptide-based Macrocycles 288

8.3 Macrocycles Targeting G-Protein Coupled Receptors(GPCRs) 289

8.3.1 Introduction 2898.3.2 Bradykinin Receptor Antagonists 2908.3.3 C5a Antagonists 2928.3.4 Chemokine Receptor Modulators: CXCR4 2948.3.5 Endothelin Antagonists 2968.3.6 Enkephalin Modulators 2998.3.7 N-Formyl Peptide Receptor 1 (FPR1)

Antagonists 3008.3.8 Ghrelin Modulators 3028.3.9 Melanocortin Receptor Modulators 304

8.3.10 m-Opioid Receptor (MOR) Modulators 3068.3.11 Motilin Modulators 3098.3.12 Somatostatin Antagonists 3108.3.13 Tachykinins: Inhibitors of NK1 3128.3.14 Vasopressin Receptor (V1a) Agonists:

FE202158 3128.4 Macrocycles Targeting Integrins 313

8.4.1 Introduction 3138.4.2 Cilengitide (81): Inhibitor of avb3,

avb5, a5b1 3148.4.3 Inhibitors of aIIbb3 (Platelet Receptor) 3158.4.4 HUN-7293: Inhibitor of VCAM 316

8.5 Macrocycles Targeting Protein–Protein Interactions(PPIs) 316

8.5.1 The Nature of PPIs 3168.5.2 SH2 Domains: Macrocyclic Modulators

of Grb2 3178.5.3 Peptidyl Prolyl Isomerases (PPIases) 3208.5.4 Macrocyclic Modulators of PDZ

Domains 3218.5.5 Inhibitors of Menin-MLL1 Interaction 3228.5.6 Sonic Hedgehog (Shh) Modulators 3238.5.7 Transporters: Novel Macrocycles Targeting

LptD 3248.6 Summary and Outlook 325References 326

Chapter 9 Macrocyclic a-Helical Peptide Drug Discovery 339Tomi K. Sawyer, Vincent Guerlavais, Krzysztof Darlak andEric Feyfant

9.1 Introduction 339

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9.2 a-Helical Interfaces in Protein–Protein DrugTarget Space 3409.2.1 Stapled Peptide Modulation of Drug

Target Space 3409.2.2 Understanding the Cell Penetration

Properties of Macrocyclic a-Helical Peptides 3429.3 Structural Diversity and Chemistry of Macrocyclic

a-Helical Peptides 3429.3.1 Hydrocarbon Stapled Peptide Chemistry 350

9.4 Biophysical and Computational Analysis ofMacrocyclic a-Helical Peptides 352

9.5 Macrocyclic a-Helical Peptide Chemical Biology andDrug Design 3559.5.1 Intracellular Therapeutic Target Drug

Discovery 3559.5.2 Extracellular Therapeutic Target Drug

Discovery 3579.6 Macrocyclic a-Helical Peptide Drug Development 358Acknowledgments 358References 358

Chapter 10 Optimizing the Permeability and Oral Bioavailability ofMacrocycles 367Alan M. Mathiowetz, Siegfried S. F. Leung andMatthew P. Jacobson

10.1 Introduction 36710.2 Pharmacokinetic Benefits of Macrocyclization 36810.3 Properties Related to Permeability and Oral

Bioavailability 37410.4 Computational Modeling of Absorption and

Permeation 38010.5 Orally Bioavailable Macrocycles 384

10.5.1 Examples of Orally BioavailableMacrocycles 384

10.5.2 Design Principles and Structure PropertyRelationships 390

10.6 Conclusions 393Acknowledgments 393References 393

Chapter 11 The Synthesis of Macrocycles for Drug Discovery 398Mark L. Peterson

11.1 Introduction 398

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11.2 Macrolactamization and Macrolactonization 39911.3 Substitution Chemistry 403

11.3.1 SN2 Reactions 40311.3.2 Nucleophilic Aromatic Substitution (SNAr) 405

11.4 Ring-Closing Metathesis 40911.5 Wittig Chemistry 41611.6 Mitsunobu Reactions 41711.7 Organometallic Methods 417

11.7.1 Palladium-mediated Reactions 41711.7.2 Ruthenium-mediated Reactions 42611.7.3 Nickel-mediated Reactions 42711.7.4 Other Organometallic Reactions 429

11.8 Cycloadditions 43111.9 Multicomponent Reactions (MCR) 436

11.10 Ring Expansion/Opening 44011.11 Reductive Amination 44311.12 Miscellaneous Methods 44511.13 Synthesis at Scale 44811.14 Macrocyclic Library Synthesis 453

11.14.1 Standard Chemistry Methods 45311.14.2 Biological-Chemical Hybrid Approaches 461

11.15 Cyclization Studies 46411.16 Conclusions 465Acknowledgements 465References 465

Subject Index 487

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