Annual Reports in Medicinal Chemistry

Contributors

Preface

Chapter One Reflections on Medicinal Chemistry at Merck, West Point

Chapter Two My Path in Seeking New Medicines

Reflections

Chapter Three Tales of Drug Discovery

1 Prostaglandins

2 Cannabinoid Analgesics

3 Hypoglycemic Agents

4 Opioid Analgesics

5 HIV Fusion Inhibitors

6 Epithelial Sodium Channel Blockers

7 Conclusions and Ramblings

Chapter Four Recent Developments in Targeting Neuroinflammation in Disease

1 Introduction

2 Ion Channels

3 Enzymes

4 Receptors

5 Concluding Remarks

Chapter Five Secretase Inhibitors and Modulators as a Disease-Modifying Approach Against Alzheimer’s Disease

1 Introduction

2 Inhibitors of GS

3 Modulators of GS

4 Inhibitors of β-Secretase

5 Concluding Remarks

Chapter Six mGluR2 Activators and mGluR5 Blockers Advancing in the Clinic for Major CNS Disorders

1 Introduction

2 Discovery and Development of mGluR2 Activators

3 Drug Discovery and Development of mGluR5 NAMs

4 Conclusion

Chapter Seven NMDA Antagonists of GluN2B Subtype and Modulators of GluN2A, GluN2C, and GluN2D Subtypes—Recent Results and Developments

1 Introduction

2 X-ray Structural Studies and Homology Modeling of NMDA Receptors

3 Channel Blockers

4 Inhibitors of GluN2B Subtype Receptor

5 Inhibitors and Modulators of GluN2A, GluN2C, and GluN2D Subtype Receptors

6 Clinical Trials

7 Conclusions

Chapter Eight Recent Advances in the Development of PET and SPECT Tracers for Brain Imaging

1 Introduction

2 PET and SPECT

3 CNS PET Tracers: General Requirements and Key Hurdles

4 Recent Advances in CNS PET Tracer Development

5 New CNS PET Tracers

6 SPECT in Brain Imaging

7 Conclusions

Chapter Nine Case History

1 Introduction

2 Rationale for Targeting FXa

3 Medicinal Chemistry Efforts Culminating in Apixaban

4 Preclinical Properties of Apixaban

5 Clinical Studies of Apixaban

6 Conclusion

Chapter Ten AMPK Activation in Health and Disease

1 Introduction

2 AMPK—Enzyme Structure and Function

3 Major AMPK-Mediated Effects on Lipid and Carbohydrate Metabolism

4 Therapeutic Potential of AMPK Activation

5 Pharmacological AMPK Activators

6 Conclusion

Chapter Eleven Type-2 Diabetes and Associated Comorbidities as an Inflammatory Syndrome

1 Introduction

2 Type-2 Diabetes

3 Diabetic Nephropathy

4 Diabetic Retinopathy

5 Diabetic Neuropathy

6 Conclusions

Chapter Twelve Beyond PPARs and Metformin

1 Introduction

2 Insulin Sensitizers

3 Conclusion

Chapter Thirteen Recent Advances in the Discovery and Development of Sphingosine-1-Phosphate-1 Receptor Agonists

1 Introduction

2 Recent Clinical Developments of S1P1 Agonists

3 Recent Preclinical Developments of S1P1 Agonists

4 Conclusions

Chapter Fourteen Bifunctional Compounds for the Treatment of COPD

1 Introduction

2 Bifunctional Strategies and Compounds

3 Conclusions

Chapter Fifteen Inflammatory Targets for the Treatment of Atherosclerosis

1 Introduction

2 Phospholipase A2

3 Leukotriene Pathway and Atherosclerosis

4 Chemokines and Atherosclerosis

5 Conclusions

Chapter Sixteen Nanotechnology Therapeutics in Oncology—Recent Developments and Future Outlook

1 Introduction

2 Passive Targeting—The EPR Effect

3 Ideal Characteristics of Nanoparticles

4 Loading of Nanoparticles

5 Types of Nanoparticles

6 The Next Generation of Nanomedicines for Oncology

7 Conclusions

Chapter Seventeen Small-Molecule Antagonists of Bcl-2 Family Proteins

1 Introduction

2 Small-Molecule Inhibitors of Bcl-2 Family Proteins

3 Conclusions

Chapter Eighteen Notch Pathway Modulators as Anticancer Chemotherapeutics

1 Introduction

2 Mechanism of Notch Signal Transduction

3 Role in Tumorigenesis

4 Inhibitors of Notch Signaling

5 Activators of Notch Signaling

6 Conclusions

Chapter Nineteen Anaplastic Lymphoma Kinase Inhibitors for the Treatment of ALK-Positive Cancers

1 Introduction

2 Crizotinib (Xalkori®)

3 Acquired Crizotinib Resistance

4 Clinical Candidates

5 Preclinical Candidates

6 Conclusions

Chapter Twenty Recent Advances in the Discovery of Dengue Virus Inhibitors

1 Introduction

2 Viral Structural Protein Targets

3 Viral Nonstructural Protein Targets

4 Host Targets

5 Conclusions

Chapter Twenty-One Nonfluoroquinolone-Based Inhibitors of Mycobacterial Type II Topoisomerase as Potential Therapeutic Agents for TB

1 Introduction

2 Inhibition at the ATP-Binding Site

3 Inhibition at the Non-ATP-Binding Site

4 Conclusions

Chapter Twenty-Two HCV Inhibition Mediated Through the Nonstructural Protein 5A (NS5A) Replication Complex

1 Introduction

2 First-Generation NS5A Inhibitors

3 Current-Generation NS5A Inhibitors

4 NS5A Structural Biology and Current Inhibitor Design

5 Clinical Progress of NS5A Inhibitors

6 Future Prospects

Chapter Twenty-Three Antibody–Drug Conjugates for Targeted Cancer Therapy

1 Introduction

2 Target Selection

3 Cytotoxic Agents and Linkers Used in ADCs

4 Intracellular Catabolism of ADCs

5 ADCs in Clinical Development

6 Conclusion

Chapter Twenty-Four 3D Cell Cultures

1 Introduction

2 3D Cell Culture: A Physiologically Relevant Biological Tool to Investigate Cellular Behavior

3 Use of 3D Cell Cultures in Drug Discovery

4 Application of 3D Cell Cultures in Various Therapeutic Areas

5 Conclusion

Chapter Twenty-Five Virally Encoded G Protein-Coupled Receptors

1 Introduction

2 Structure, Function, and Physiological Consequences of vGPCRs

3 Allosteric Modulators of vGPCRs

4 Allosteric Modulators of vGPCRs at Work

5 Conclusions

Chapter Twenty-Six Recent Advances in Wnt/β-Catenin Pathway Small-Molecule Inhibitors

1 Introduction

2 Regulation of β-Catenin

3 Selective Small-Molecule Antagonists of Wnt/β-Catenin Signaling

4 Conclusions

Chapter Twenty-Seven Targeted Covalent Enzyme Inhibitors

1 Introduction

2 Functionally Reversible Covalent Enzyme Inhibitors

3 Functionally Irreversible Covalent Enzyme Inhibitors

4 Conclusions

Chapter Twenty-Eight Drug Design Strategies for GPCR Allosteric Modulators

1 Introduction

2 Structure–Activity Relationships of Allosteric Ligands

3 Functional Selectivity

4 What to Optimize: IC50? EC50? EMAX? Fold-Shift? Log(αβ)?

5 Do In Vitro Profiles Translate to In Vivo Pharmacology?

6 Assessing Allosteric Site Occupancy Through Radioligands and Pet Agents

7 Medicinal Chemistry Strategies for Allosteric Ligands

8 Conclusions

Chapter Twenty-Nine Progress in the Development of Non-ATP-Competitive Protein Kinase Inhibitors for Oncology

1 Introduction

2 Inhibition of Cyclin-Dependent Kinases Through the Cyclin Groove

3 Alternative Strategies in the Development of Non-ATP-Competitive CDK Inhibitors

4 Polo-Box Domain Inhibitors of Polo-Like Kinases

5 Conclusions

Chapter Thirty New Chemical Entities Entering Phase III Trials in 2011

1 Selection Criteria

2 Facts and Figures

3 NCE List

Chapter Thirty-One To Market, To Market—2011

Overview

1 Abiraterone Acetate (Anticancer)7–14

2 Aflibercept (Ophthalmologic, Macular Degeneration)15–22

3 Apixaban (Antithrombotic)23–37

4 Avanafil (Male Sexual Dysfunction)38–45

5 Azilsartan Medoxomil (Antihypertensive)46–52

6 Belatacept (Immunosupressive)53–61

7 Belimumab (Immunosuppressive, Lupus)62–68

8 Boceprevir (Antiviral)69–77

9 Brentuximab Verdotin (Anticancer)78–83

10 Crizotinib (Anticancer)84–89

11 Edoxaban (Antithrombotic)24–27,32,90–96

12 Eldecalcitol (Osteoporosis)97–102

13 Fidaxomicin (Antibacterial)103–108

14 Gabapentin Enacarbil (Restless Leg Syndrome)109–117

15 Iguratimod (Antiarthritic)118–124

16 Ipilimumab (Anticancer)78,125–131

17 Linagliptin (Antidiabetic)132–140

18 Mirabegron (Urinary Tract/Bladder Disorders)141–144

19 Retigabine (Anticonvulsant)145–156

20 Rilpivirine (Antiviral)4,157–165

21 Ruxolitinib (Anticancer)166–171

22 Tafamidis Meglumine (Neurodegeneration)172–176

23 Telaprevir (Antiviral)69,70,177–183

24 Vandetanib (Anticancer)184–189

25 Vemurafenib (Anticancer)190–195

26 Vilazodone Hydrochloride (Antidepressant)196–204

Keyword Index, Volume 47

Cumulative Chapter Titles Keyword Index, Volume 1 – 47

Cumulative NCE Introduction Index, 1983-2011

Cumulative NCE Introduction Index, 1983-2011 (by indication)