Annual Reports in Medicinal Chemistry

1st Edition, Volume 49 - September 24, 2014
Editor: Manoj C Desai
Language: English
Paperback ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 1 6 7 - 7
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 3 7 2 - 5

Annual Reports in Medicinal Chemistry provides timely and critical reviews of important topics in medicinal chemistry with an emphasis on emerging topics in the biological scienc… Read more

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

Preface
Personal Essays
- Chapter One: A Personal Essay: My Experiences in the Pharmaceutical Industry
- Chapter Two: Adventures in Medicinal Chemistry: A Career in Drug Discovery
  - Acknowledgments
Section 1: Central Nervous System Diseases
- Chapter Three: Natural and Synthetic Neuroactive Steroid Modulators of GABA_A and NMDA Receptors
  - Abstract
  - 1 Introduction
  - 2 NAS Modulators of the GABA_A Receptor
  - 3 NAS Modulators of the NMDA Receptor
  - 4 Conclusions
- Chapter Four: Development of LRRK2 Kinase Inhibitors for Parkinson's Disease
  - Abstract
  - 1 Introduction
  - 2 LRRK2 Biology
  - 3 Medicinal Chemistry
  - 4 Preclinical Animal Models
  - 5 Conclusions
- Chapter Five: Stimulating Neurotrophin Receptors in the Treatment of Neurodegenerative Disorders
  - Abstract
  - 1 Introduction
  - 2 NTs and NT Receptors—Structure and Function
  - 3 Role of NTs and Their Receptors in Neurodegenerative Disorders
  - 4 Pharmacological Activators of NT Receptors
  - 5 Conclusion
Section 2: Cardiovascular and Metabolic Diseases
- Chapter Six: Small-Molecule Modulators of GPR40 (FFA1)
  - Abstract
  - 1 Introduction
  - 2 Recent Discoveries in GPR40 Biology
  - 3 GPR40 Partial Agonists
  - 4 GPR40 Full Agonists
  - 5 Conclusions
- Chapter Seven: Recent Advances in the Development of P2Y₁₂ Receptor Antagonists as Antiplatelet Agents
  - Abstract
  - 1 Introduction
  - 2 FDA-Approved P2Y₁₂ Receptor Antagonists
  - 3 New P2Y₁₂ Receptor Antagonists
  - 4 Clinical Application
  - 5 Conclusions
- Chapter Eight: Current Approaches to the Treatment of Atrial Fibrillation
  - Abstract
  - 1 Introduction
  - 2 Atrial-Selective Agents Versus Non-selective Agents
  - 3 Clinical Updates
  - 4 Preclincal Advances
  - 5 Conclusion
Section 3: Inflammation/Pulmonary/GI Diseases
- Chapter Nine: Advances in the Discovery of Small-Molecule IRAK4 Inhibitors
  - Abstract
  - 1 Introduction
  - 2 Rationale for Targeting IRAK4 in Inflammatory Diseases
  - 3 IRAK4 Structure
  - 4 Recent Medicinal Chemistry Efforts
  - 5 Conclusions
- Chapter Ten: H₄ Receptor Antagonists and Their Potential Therapeutic Applications
  - Abstract
  - 1 Introduction
  - 2 Antagonists of the H₄ Receptor
  - 3 Role of the Histamine H₄ Receptor in Disease Models
  - 4 Clinical Development of H₄ Receptor Antagonists
  - 5 Conclusions
- Chapter Eleven: Urate Crystal Deposition Disease and Gout—New Therapies for an Old Problem
  - Abstract
  - 1 Introduction
  - 2 Therapeutics for Gout by Clinical Manifestation
  - 3 Conclusions
Section 4: Oncology
- Chapter Twelve: p53–MDM2 and MDMX Antagonists
  - Abstract
  - 1 Introduction
  - 2 MDM2 Antagonists
  - 3 MDMX Antagonists
  - 4 Conclusion
- Chapter Thirteen: Modulators of Atypical Protein Kinase C as Anticancer Agents
  - Abstract
  - 1 Introduction
  - 2 Atypical Protein Kinase C Isoforms
  - 3 Disease Linkage of Atypical PKCs
  - 4 Non-ATP-Binding Site Inhibitors
  - 5 ATP-Binding Site Inhibitors
  - 6 Conclusions
Section 5: Infectious Diseases
- Chapter Fourteen: Advancement of Cell Wall Inhibitors in Mycobacterium tuberculosis
  - Abstract
  - 1 Introduction
  - 2 Cell Wall Inhibitors
  - 3 Conclusions
- Chapter Fifteen: Nucleosides and Nucleotides for the Treatment of Viral Diseases
  - Abstract
  - 1 Introduction
  - 2 Human Immunodeficiency Virus
  - 3 Hepatitis B Virus
  - 4 Hepatitis C Virus
  - 5 Dengue Virus
  - 6 Conclusion
- Chapter Sixteen: Advances in Inhibitors of Penicillin-Binding Proteins and β-Lactamases as Antibacterial Agents
  - Abstract
  - 1 Introduction
  - 2 PBP Inhibitors
  - 3 β-Lactamase Inhibitors
  - 4 Conclusions and Outlook
Section 6: Topics in Biology
- Chapter Seventeen: Tumor Microenvironment as Target in Cancer Therapy
  - Abstract
  - 1 Introduction
  - 2 Cancer-Promoting Enzymes and Inhibitors
  - 3 Carbamoylphosphonates: Inhibitors of Extracellular Zinc–Enzymes
  - 4 Conclusions and Outlook
  - Acknowledgments
- Chapter Eighteen: Novel Screening Paradigms for the Identification of Allosteric Modulators and/or Biased Ligands for Challenging G-Protein-Coupled Receptors
  - Abstract
  - 1 Introduction
  - 2 Allosteric Modulators
  - 3 Biased Ligands
  - 4 Ab Discovery as Novel AMs/BLs
  - 5 Conclusions
- Chapter Nineteen: Mer Receptor Tyrosine Kinase: Therapeutic Opportunities in Oncology, Virology, and Cardiovascular Indications
  - Abstract
  - 1 Introduction
  - 2 Mer Biological Function and Therapeutic Opportunities
  - 3 Small Molecule Mer Inhibitors
  - 4 Future Directions and Conclusions
Section 7: Topics in Drug Design and Discovery
- Chapter Twenty: Disease-Modifying Agents for the Treatment of Cystic Fibrosis
  - Abstract
  - 1 Introduction
  - 2 Treating Class I Defects
  - 3 Treating Class II Defects (Correctors)
  - 4 Treating Class III Defects (Potentiators)
  - 5 Compounds with Dual Activity
  - 6 Conclusions
- Chapter Twenty-One: Advancements in Stapled Peptide Drug Discovery & Development
  - Abstract
  - 1 Introduction
  - 2 Beneficial Effects Attributed to the Hydrocarbon Staple
  - 3 Drug Discovery: Preclinical Research
  - 4 Drug Development and P53 Reactivation
  - 5 Concluding Remarks
- Chapter Twenty-Two: Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development
  - Abstract
  - 1 Introduction
  - 2 Identification of CYP-Modified Natural Products as Drug Leads
  - 3 Identification of Pharmacologically Active Metabolites of Known Drugs
  - 4 Future Directions and Conclusions
  - Acknowledgments
Section 8: Case Histories and NCEs
- Chapter Twenty-Three: Case History: Forxiga^TM (Dapagliflozin), a Potent Selective SGLT2 Inhibitor for Treatment of Diabetes
  - Abstract
  - 1 Introduction
  - 2 Renal Recovery of Glucose
  - 3 O-Glucoside SGLT2 Inhibitors
  - 4 C-Aryl Glucoside SGLT2 Inhibitors
  - 5 Synthesis of Dapagliflozin
  - 6 Preclinical Profiling Studies with Dapagliflozin
  - 7 Clinical Studies with Dapagliflozin
  - 8 Conclusion
- Chapter Twenty-Four: Case History: Kalydeco® (VX-770, Ivacaftor), a CFTR Potentiator for the Treatment of Patients with Cystic Fibrosis and the G551D-CFTR Mutation
  - Abstract
  - 1 Introduction
  - 2 CFTR as a Drug Discovery Target
  - 3 The Discovery of CFTR Potentiators
  - 4 Medicinal Chemistry Efforts Culminating in Ivacaftor
  - 5 Preclinical Properties of Ivacaftor
  - 6 Formulation Development
  - 7 Clinical Studies
  - 8 Conclusion
- Chapter Twenty-Five: Case History: Xeljanz™ (Tofacitinib Citrate), a First-in-Class Janus Kinase Inhibitor for the Treatment of Rheumatoid Arthritis
  - Abstract
  - 1 Introduction
  - 2 Rationale for Targeting the JAK Enzymes
  - 3 Medicinal Chemistry Efforts Culminating in the Identification of Tofacitinib¹⁵
  - 4 Selectivity and Pharmacology of Tofacitinib
  - 5 Preclinical Properties of Tofacitinib
  - 6 Clinical Properties of Tofacitinib
  - 7 Conclusions
  - Acknowledgments
- Chapter Twenty-Six: New Chemical Entities Entering Phase III Trials in 2013
  - Abstract
- Chapter Twenty-Seven: To Market, To Market—2013
  - Abstract
  - Overview
  - 1 Acotiamide (Dyspepsia)¹¹^–¹⁷
  - 2 Ado-Trastuzumab Emtansine (Anticancer)¹⁸^–²²
  - 3 Afatinib (Anticancer)²³^–²⁹
  - 4 Canagliflozin (Antidiabetic)³⁰^–⁴²
  - 5 Cetilistat (Antiobesity)⁴³^–⁵²
  - 6 Cobicistat (Antiviral, Pharmacokinetic Enhancer)⁵³^–⁵⁹
  - 7 Dabrafenib (Anticancer)⁶⁰^–⁶⁵
  - 8 Dimethyl Fumarate (Multiple Sclerosis)⁶⁶^–⁸⁰
  - 9 Dolutegravir (Antiviral)⁸¹^–⁹¹
  - 10 Efinaconazole (Antifungal)⁹²^–⁹⁸
  - 11 Elvitegravir (Antiviral)⁹⁹^–¹⁰⁸
  - 12 Ibrutinib (Anticancer)¹⁰⁹^–¹¹⁴
  - 13 Istradefylline (Parkinson's Disease)¹¹⁵^–¹²²
  - 14 Lixisenatide (Antidiabetic)¹²³^–¹³¹
  - 15 Macitentan (Antihypertensive)¹³²^–¹³⁸
  - 16 Metreleptin (Lipodystrophy)¹³⁹^–¹⁵⁰
  - 17 Mipomersen (Antihypercholesteremic)¹⁵¹^–¹⁵⁸
  - 18 Obinutuzumab (Anticancer)¹⁵⁹^–¹⁶⁴
  - 19 Olodaterol (Chronic Obstructive Pulmonary Disease)¹⁶⁵^–¹⁷⁴
  - 20 Ospemifene (Dyspareunia)¹⁷⁵^–¹⁸¹
  - 21 Pomalidomide (Anticancer)¹⁸²^–¹⁹⁵
  - 22 Riociguat (Pulmonary Hypertension)¹⁹⁶^–²⁰³
  - 23 Saroglitazar (Antidiabetic)²⁰⁴^–²¹²
  - 24 Simeprevir (Antiviral)²¹⁴^–²²³
  - 25 Sofosbuvir (Antiviral)²²⁴^–²³⁵
  - 26 Trametinib (Anticancer)²³⁶^–²⁴²
  - 27 Vortioxetine (Antidepressant)²⁴³^–²⁵²
Keyword Index, Volume 49
Cumulative Chapter Titles Keyword Index, Volume 1 – 49
Cumulative NCE Introduction Index, 1983–2013
Cumulative NCE Introduction Index, 1983–2013 (By Indication)

Manoj C 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

Life sciences

Physical sciences & Engineering

Social sciences & Humanities

Health