Annual Reports in Medicinal Chemistry

Contributors

Preface

Personal Essays

Chapter One. Challenges in Drug Discovery at Schering–Plough Research Institute: A Personal Reflection

Abstract

Acknowledgments

References

Chapter Two. My Perspective on Time, Managers—and Scientific Fun

1 Controlling Your Scientific Life: Time Management

2 Foster Innovation with Scientific Fun

3 A Good Manager is a Scientist’s Best Friend

References

Chapter Three. A Career in Medicinal Chemistry—A Journey in Drug Discovery

Abstract

1 Early Days in Nucleoside, Nucleotide, and Nucleic Acid Chemistry

2 Antivirals

3 Elastase Inhibitors

4 Substance P Antagonists and the Discovery of Aprepitant and Fosaprepitant

5 Hypoglycemic Agents and the Discovery of Sitagliptin

6 Conclusions

References

Section 1: Central Nervous System Diseases

Chapter Four. Selective Inhibitors of PDE2, PDE9, and PDE10: Modulators of Activity of the Central Nervous System

Abstract

1 Introduction

2 Phosphodiesterase (PDE) Structures

3 PDE2 Inhibitors and Dual PDE2 + PDE10 Inhibitors

4 PDE9 Inhibitors

5 PDE10 Inhibitors

6 Conclusions

References

Chapter Five. Beyond Secretases: Kinase Inhibitors for the Treatment of Alzheimer’s Disease

Abstract

1 Introduction

2 Inhibitors of Dual-Specificity Kinases

3 Inhibitors of Serine–Threonine Kinases

4 Conclusions

References

Chapter Six. Orexin Receptor Antagonists in Development for Insomnia and CNS Disorders

Abstract

1 Introduction

2 Clinical Programs

3 Preclinical Programs

4 Potential Indications Beyond Sleep

5 Concluding Remarks

References

Section 2: Cardiovascular and Metabolic Diseases

Chapter Seven. Discovery and Development of Prolylcarboxypeptidase Inhibitors for Cardiometabolic Disorders

Abstract

1 Introduction

2 PRCP Function and Structure

3 PRCP: Peptide Processing and Regulation

4 PRCP Inhibitors as Antiobesity Agents

5 Conclusions

References

Chapter Eight. Molecular Targeting of Imaging and Drug Delivery Probes in Atherosclerosis

Abstract

1 Introduction

2 Chemical and Imaging Approaches

3 Targeting of Vascular Adhesion Molecules and Markers of Inflammation

4 Conclusions

References

Chapter Nine. Oral GLP-1 Modulators for the Treatment of Diabetes

Abstract

1 Introduction

2 Formulation of Peptidic Agonists

3 Active Transport of Peptidic Agonists

4 Small Molecule Agonists of the GLP-1R

5 Conclusion

References

Section 3: Inflammation Pulmonary GI Diseases

Chapter Ten. Recent Advances in the Discovery and Development of CCR1 Antagonists

Abstract

1 Introduction

2 Small Molecule CCR1 Antagonists

3 Clinical Update

4 Outlook

References

Chapter Eleven. Emerging Targets for the Treatment of Idiopathic Pulmonary Fibrosis

Abstract

1 Introduction

2 G Protein-Coupled Receptors (GPCRs)

3 Extracellular Crosslinking Enzymes

4 Kinase Inhibitors

5 Enzymes

6 Lysophospholipid Mediators

7 Conclusions

References

Chapter Twelve. Targeting the Nuclear Hormone Receptor RORγt for the Treatment of Autoimmune and Inflammatory Disorders

Abstract

1 Introduction

2 Target Validation of RORγ/γt in Disease Models

3 Safety Concerns Targeting RORγt

4 RORγt Structure

5 Small-Molecule Antagonists of RORγt

6 Conclusions

References

Section 4: Oncology

Chapter Thirteen. Recent Advances in Small-Molecule Modulation of Epigenetic Targets: Discovery and Development of Histone Methyltransferase and Bromodomain Inhibitors

Abstract

1 Introduction

2 Histone Modifications

3 Histone Methyltransferase Inhibitors

4 Bromodomain Inhibitors

5 Conclusions and Outlook

References

Chapter Fourteen. Inhibition of Ubiquitin Proteasome System Enzymes for Anticancer Therapy

Abstract

1 Introduction

2 Inhibitors of 20S CP Peptidases

3 Inhibitors of Ubiquitin Conjugation

4 Ubiquitin-Interacting Proteins and Chaperones

5 Conclusions and Future Directions

References

Chapter Fifteen. Targeting Protein–Protein Interactions to Treat Cancer—Recent Progress and Future Directions

Abstract

1 Introduction

2 PPIs Important to the Growth and Spread of Cancer

3 Challenges in Targeting PPIs

4 Methods for Discovering Small-Molecule Inhibitors of PPIs

5 Examples of Targeting PPIs Important to Oncology

6 Two Recent Successes

7 Future Developments

8 Conclusions

References

Section 5: Infectious Diseases

Chapter Sixteen. Recent Progress in the Discovery of Neuraminidase Inhibitors as Anti-influenza Agents

Abstract

1 Introduction

2 Inhibitors Based upon Flexible Scaffolds

3 Inhibitors Based upon Rigid, Planar Scaffolds

4 Natural Products as Potential Anti-influenza Drug Leads

5 Conclusions and Outlook

References

Chapter Seventeen. Novel Therapeutics in Discovery and Development for Treatment of Chronic HBV Infection

Abstract

1 Introduction of the HBV Life Cycle

2 Current Standard of Care Therapeutics for HBV Infection

3 Selected Direct Acting Antivirals and Immune Modulators Under Clinical Development

4 Nonnucleos(t)ide Small Molecule HBV Inhibitors in Discovery Stage

5 Conclusion and Outlook

Acknowledgment

References

Chapter Eighteen. Special Challenges to the Rational Design of Antibacterial Agents

Abstract

1 Introduction

2 Specific Issues in Antibacterial Drug Design

3 Practical Approaches

4 Review of Recent Applications

5 Conclusions

References

Section 6: Topics in Biology

Chapter Nineteen. Recent Advances in Small Molecule Target Identification Methods

Abstract

Abbreviations

1 Introduction

2 Affinity-Based Proteomics

3 In Silico Target Prediction

4 Drug Resistance and Sequencing-Based Target Identification

5 Yeast-Based Approaches

6 Conclusions

References

Chapter Twenty. Neuroinflammation in Mood Disorders: Mechanisms and Drug Targets

Abstract

Abbreviations

1 Introduction

2 Inflammasome Pathway and Cytokine Modulation

3 Tryptophan Metabolic Pathway

4 Concluding Remarks

References

Section 7: Topics in Drug Design and Discovery

Chapter Twenty-One. Inhibitors of hERG Channel Trafficking: A Cryptic Mechanism for QT Prolongation

Abstract

1 Introduction

2 Biochemical Pharmacology of the hERG K⁺ Channel

3 Inhibitors of hERG Trafficking

4 Screening Assays for hERG Trafficking Inhibition

5 Conclusion

References

Chapter Twenty-Two. Recent Progress in Small-Molecule Agents Against Age-Related Macular Degeneration

Abstract

1 Introduction

2 Anti-Angiogenesis Agents

3 Visual Cycle Inhibitors

4 Complement Pathway Inhibitors

5 Conclusions

References

Chapter Twenty-Three. Synthetic Macrocycles in Small-Molecule Drug Discovery

Abstract

1 Introduction

2 Hepatitis C Virus NS3/4A Protease and NS5b Polymerase

3 Kinase Inhibitors with Improved Selectivity

4 Ghrelin Agonists: Discovery of TZP-101

5 Stapled Peptides

6 Conclusion

References

Chapter Twenty-Four. Glossary of Terms Used in Medicinal Chemistry Part II (IUPAC Recommendations 2013)

Abstract

1 Introduction

2 Alphabetical Entries

Acknowledgment

References

Section 8: Case Histories and NCEs

Chapter Twenty-Five. Case History: Xalkori™ (Crizotinib), a Potent and Selective Dual Inhibitor of Mesenchymal Epithelial Transition (MET) and Anaplastic Lymphoma Kinase (ALK) for Cancer Treatment

Abstract

1 Introduction

2 Targeting Met in Cancer

3 Targeting ALK in Cancer

4 Medicinal Chemistry Efforts in Discovering Crizotinib

5 Kinase Selectivity of Crizotinib

6 Preclinical Pharmacology of Crizotinib

7 Crizotinib Human Clinical Efficacy

8 Conclusions

References

Chapter Twenty-Six. Case History: Vemurafenib, a Potent, Selective, and First-in-Class Inhibitor of Mutant BRAF for the Treatment of Metastatic Melanoma

Abstract

1 Introduction

2 Rationale for Targeting Mutant BRAF

3 Medicinal Chemistry Efforts Culminating in Vemurafenib

4 Preclinical Characterization of Vemurafenib

5 Clinical Studies of Vemurafenib

6 Conclusions

References

Chapter Twenty-Seven. New Chemical Entities Entering Phase III Trials in 2012

Abstract

References

Chapter Twenty-Eight. To Market, To Market—2012

Abstract

1 Overview

2 Aclidinium Bromide (Chronic Obstructive Pulmonary Disease)

3 Anagliptin (Antidiabetic)

4 Axitinib (Anticancer)

5 Bedaquiline (Antibacterial)

6 Bosutinib (Anticancer)

7 Cabozantinib (Anticancer)

8 Carfilzomib (Anticancer)

9 Crofelemer (Antidiarrheal)

10 Dapagliflozin (Antidiabetic)

11 Enzalutamide (Anticancer)

12 Ingenol Mebutate (Anticancer)

13 Ivacaftor (Cystic Fibrosis)

14 Linaclotide (Irritable Bowel Syndrome)

15 Lomitapide Mesylate (Antihypercholesteremic)

16 Lorcaserin Hydrochloride (Antiobesity)

17 Mogamulizumab (Anticancer)

18 Omacetaxine Mepesuccinate (Anticancer)

19 Pasireotide (Cushing’s Disease)

20 Peginesatide (Hematopoietic)

21 Perampanel (Anticonvulsant)

22 Pertuzumab (Anticancer)

23 Pixantrone Dimaleate (Anticancer)

24 Ponatinib (Anticancer)

25 Radotinib (Anticancer)

26 Regorafenib (Anticancer)

27 Teduglutide (Short Bowel Syndrome)

28 Teneligliptin (Antidiabetic)

29 Teriflunomide (Multiple Sclerosis)

30 Tofacitinib (Antiarthritic)

31 Vismodegib (Anticancer)

References

Keyword Index, Volume 48

Cumulative Chapter Titles Keyword Index, Volume 1 – 48

Cumulative NCE Introduction Index, 1983–2012

Cumulative NCE Introduction Index, 1983–2012 (by indication)