Annual Reports in Medicinal Chemistry - 1st Edition - ISBN: 9780124171503, 9780124171510

Annual Reports in Medicinal Chemistry, Volume 48

1st Edition

Serial Editors: Manoj Desai
eBook ISBN: 9780124171510
Paperback ISBN: 9780124171503
Imprint: Academic Press
Published Date: 8th October 2012
Page Count: 672
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Table of Contents

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)


Description

Annual Reports in Medicinal Chemistry provides timely and critical reviews of important topics in medicinal chemistry together with an emphasis on emerging topics in the biological sciences, which are expected to provide the basis for entirely new future therapies.

Key Features

  • Annual Reports in Medicinal Chemistry provides timely and critical reviews and this volume covers important topics such as drug Discovery, Idiopathic Pulmonary Fibrosis and Neuraminidase Inhibitors

Readership

medicinal, pharmaceutical, and organic chemists


Details

No. of pages:
672
Language:
English
Copyright:
© Academic Press 2013
Published:
Imprint:
Academic Press
eBook ISBN:
9780124171510
Paperback ISBN:
9780124171503

Reviews

"This series is one of the very few annual publications which justify the title of an absolute must for the pharmacologist, chemist, or physician who is interested in the chemistry of drug development." --Enzymeologia


About the Serial Editors

Manoj Desai Serial Editor

Dr. Manoj Desai began his career in the pharmaceutical industry at Pfizer Inc, Central Research Division, Groton, CT (1986-1994) before moving to Chiron Corporation (1994-2003) as Director of medicinal chemistry; he was promoted to Vice President, lead discovery and medicinal chemistry (2000). In October 2003, he was appointed Vice President of medicinal chemistry at Gilead Sciences. At Pfizer, he was responsible for the medicinal chemistry efforts that lead to the discovery of oral Substance P antagonist CP-99994 which became the basis for the discovery of the new anti-emetics. At Chiron he formulated macrobead technology for the synthesis and screening of compound libraries for HTS and built the medicinal chemistry department with focus on kinase inhibitors. At Gilead, he was an active proponent to develop a pharmacoenhancer devoid of antiviral activity to improve the pharmacokinetics of integrase inhibitor elvitegravir. These efforts led to the discovery of Cobicistat which is one of components of StribildTM that was approved by FDA in August 2012 for the treatment of HIV infection. He is co-inventor on patents of Cobicistat (US 8,148,374), StribildTM and Ledipasvir (US 8,273,341; Phase III). Furthermore, his group at Gilead has advanced numerous compounds into clinical development for the treatment of antiviral diseases, cancer and cardiovascular diseases.

Dr. Desai obtained Ph.D. in organic chemistry from the M.S. University of Baroda in 1981 working with Dr. Sukh Dev and then carried out post-doctoral fellowships at Purdue University working with Professor Herbert C. Brown (19981-1983) and at Harvard University with Professor Elias J. Corey (1983-1986). During his postdoctoral studies, he worked on natural product isolation, development of asymmetric synthetic methods using organoboranes and total synthesis of complex natural products such as retigeranic acid, -trans bergamotene and ginkgolide B.

He has co-authored >60 publications in peer reviewed journals and is an inventor on >25 issued patents. Furthermore, Dr. Desai is Editor-in-Chief for Annual Reports in Medicinal chemistry (2012-current), and have co-edited Comprehensive Medicinal Chemistry II (volume 7). In 2013, he co-edited book titled “Successful Strategies for the Discovery of Antiviral Drugs”.

Affiliations and Expertise

Gilead Sciences, Inc., Foster City, CA, USA