Annual Reports in Medicinal Chemistry

Annual Reports in Medicinal Chemistry

1st Edition - October 8, 2012

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  • Editor: Manoj Desai
  • eBook ISBN: 9780124171510
  • Paperback ISBN: 9780124171503

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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

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)

Product details

  • No. of pages: 672
  • Language: English
  • Copyright: © Academic Press 2013
  • Published: October 8, 2012
  • Imprint: Academic Press
  • eBook ISBN: 9780124171510
  • Paperback ISBN: 9780124171503

About the Serial Editor

Manoj Desai

Manoj Desai

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

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