Front Cover

Annual Reports in Medicinal Chemistry

Copyright

Contents

Contributors

Preface

Personal Essays

Chapter One: A Personal Essay: My Experiences in the Pharmaceutical Industry

References

Chapter Two: Adventures in Medicinal Chemistry: A Career in Drug Discovery

Acknowledgments

References

Section 1: Central Nervous System Diseases

Chapter Three: Natural and Synthetic Neuroactive Steroid Modulators of GABAA and NMDA Receptors

1. Introduction

2. NAS Modulators of the GABAA Receptor

2.1. Endogenous NAS Modulators of the GABAA Receptor

2.2. Synthetic NAS Modulators of the GABAA Receptor

2.2.1. Anesthetics

2.2.2. Compounds Suitable for Nonanesthetic Indications

3. NAS Modulators of the NMDA Receptor

4. Conclusions

References

Chapter Four: Development of LRRK2 Kinase Inhibitors for Parkinson´s Disease

1. Introduction

2. LRRK2 Biology

3. Medicinal Chemistry

3.1. LRRK2 Patent Space Analysis

3.2. Chemical Scaffolds

3.2.1. Repurposed Kinase Inhibitors

3.2.2. First-Generation LRRK2-Focused Kinase Inhibitors

3.2.3. Second-Generation LRRK2-Focused Kinase Inhibitors

3.2.4. Third-Generation LRRK2-Focused Kinase Inhibitors

4. Preclinical Animal Models

5. Conclusions

References

Chapter Five: Stimulating Neurotrophin Receptors in the Treatment of Neurodegenerative Disorders

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

4.1. Peptidic Activators

4.2. Small-Molecule Activators

5. Conclusion

References

Section 2: Cardiovascular and Metabolic Diseases

Chapter Six: Small-Molecule Modulators of GPR40 (FFA1)

1. Introduction

2. Recent Discoveries in GPR40 Biology

3. GPR40 Partial Agonists

3.1. TAK-875

3.2. AMG 837

3.3. LY2881835

4. GPR40 Full Agonists

5. Conclusions

References

Chapter Seven: Recent Advances in the Development of P2Y12 Receptor Antagonists as Antiplatelet Agents

1. Introduction

2. FDA-Approved P2Y12 Receptor Antagonists

2.1. Thienopyridines

2.2. ATP Analogs

3. New P2Y12 Receptor Antagonists

3.1. ATP Analogs

3.2. Thienopyridines

3.3. Miscellaneous Scaffolds

3.3.1. Phenylpyrazole Glutamic Acid Piperazines

3.3.2. 6-Aminonicotinates

4. Clinical Application

5. Conclusions

References

Chapter Eight: Current Approaches to the Treatment of Atrial Fibrillation

1. Introduction

2. Atrial-Selective Agents Versus Non-selective Agents

2.1. Current Standard of Care

2.2. Mechanism and Atrial-Specific Ion Channels

3. Clinical Updates

3.1. Non-selective Agents

3.2. Atrial-Selective Agents

3.2.1. IKur Inhibitors

3.2.2. IKAch Inhibitors

4. Preclincal Advances

4.1. IKur Inhibitors

4.1.1. Thienopyrimidines and Thienopyrazoles

4.1.2. Imidazolidinones

4.1.3. Indazole and Pyrrolopyrimidines

4.1.4. Phenylsulfonamides

4.1.5. Phenylcyclohexanes and gem-Dimethyl Isoindolinone

4.1.6. Benzodiazepines

4.2. IKAch Inhibitors

4.2.1. Benzamides

5. Conclusion

References

Section 3: Inflammation/Pulmonary/GI Diseases

Chapter Nine: Advances in the Discovery of Small-Molecule IRAK4 Inhibitors

1. Introduction

2. Rationale for Targeting IRAK4 in Inflammatory Diseases

2.1. TLR and IL-1R Signaling

2.2. Human IRAK4-Deficient Patients

2.3. Genetic Validation

2.4. TLR and IL-1-Targeted Therapies

2.5. IRAK4 and Cancer

3. IRAK4 Structure

4. Recent Medicinal Chemistry Efforts

4.1. Benzimidazoles

4.2. Thiazole, Pyridyl, and Oxazole Amides

4.3. Pyrazolo and Thiophene Fused Pyrimidine Amides

4.4. Pyridyl Amines

4.5. 6,5-Fused Tricyclic Thienopyrimidines and Related Heterocycles

4.6. Other Heterocyclic Cores

5. Conclusions

References

Chapter Ten: H4 Receptor Antagonists and Their Potential Therapeutic Applications

1. Introduction

1.1. Histamine Receptor Family

1.2. Expression and Function of the Histamine H4 Receptor

2. Antagonists of the H4 Receptor

2.1. Indole and Benzimidazole Amide Ligands

2.2. Dibenzodiazepine, Quinoxalinone, and Quinazoline Ligands

2.3. Pyrimidine-Based Ligands

3. Role of the Histamine H4 Receptor in Disease Models

3.1. Acute Inflammation and Inflammatory Pain

3.2. Rheumatoid Arthritis

3.3. Asthma

3.4. Pruritis

4. Clinical Development of H4 Receptor Antagonists

5. Conclusions

References

Chapter Eleven: Urate Crystal Deposition Disease and Gout-New Therapies for an Old Problem

1. Introduction

2. Therapeutics for Gout by Clinical Manifestation

2.1. Gout Flares

2.1.1. Nonsteroidal Anti-Inflammatory Drugs

2.1.2. Colchicine

2.1.3. Glucocorticoids

2.1.4. IL-1 Blockade

2.1.5. Phosphodiesterase-4

2.1.6. Anti-C5a Antibody

2.1.7. CXCR2

2.2. Hyperuricemia

2.2.1. Drugs Blocking Uric Acid Production

2.2.1.1. XO Inhibition

2.2.1.2. Purine Nucleoside Phosphorylase Inhibition

2.2.1.3. Concentrative Nucleoside Transporter Type 2

2.2.2. Drugs Increasing Uric Acid Excretion

2.2.3. Drugs Catalyzing Uric Acid Metabolism

3. Conclusions

References

Section 4: Oncology

Chapter Twelve: p53-MDM2 and MDMX Antagonists

1. Introduction

1.1. Importance of p53/MDM2/MDMX in Tumor Suppression (p53 Pathway Regulation)

1.2. The p53/MDM2/MDMX Interaction (Crystal Structures)

2. MDM2 Antagonists

2.1. Nutlin-Type Compounds

2.2. Imidazoles

2.3. Imidazothiazoles

2.4. Benzodiazepines

2.5. Spirooxindoles

2.6. Isoindolones

2.7. Indole-2-Carboxylic Acid Derivatives

2.8. Pyrrolidinones

2.9. Pyrrolidines

2.10. Isoquinolines and Piperidinones

2.11. Peptides

2.12. Miscellaneous Compounds

3. MDMX Antagonists

3.1. Imidazoles

3.2. Miscellaneous Compounds

4. Conclusion

References

Chapter Thirteen: Modulators of Atypical Protein Kinase C as Anticancer Agents

1. Introduction

1.1. Overview of Protein Kinase C Isoforms

2. Atypical Protein Kinase C Isoforms

2.1. aPKC Activation Mechanisms

2.2. aPKC Structure

2.3. aPKC Function

3. Disease Linkage of Atypical PKCs

3.1. Oncology

3.2. Metabolic Diseases

3.3. Other Indications

4. Non-ATP-Binding Site Inhibitors

4.1. PB1 Domain of aPKC (Gold Complexes)

4.2. C-terminal Lobe of the Catalytic Domain of aPKC

4.3. aPKC Pseudosubstrate Binding Site

4.4. Allosteric PIF-1 Domain Binding

4.5. Undefined Binding Modes

5. ATP-Binding Site Inhibitors

6. Conclusions

References

Section 5: Infectious Diseases

Chapter Fourteen: Advancement of Cell Wall Inhibitors in Mycobacterium tuberculosis

1. Introduction

2. Cell Wall Inhibitors

2.1. InhA

2.2. DprE1

2.3. MmpL3

2.4. Peptidoglycan Synthesis

2.5. Emerging Targets

3. Conclusions

References

Chapter Fifteen: Nucleosides and Nucleotides for the Treatment of Viral Diseases

1. Introduction

2. Human Immunodeficiency Virus

3. Hepatitis B Virus

4. Hepatitis C Virus

5. Dengue Virus

6. Conclusion

References

Chapter Sixteen: Advances in Inhibitors of Penicillin-Binding Proteins and β-Lactamases as Antibacterial Agents

1. Introduction

2. PBP Inhibitors

2.1. β-Lactam-Based Inhibitors

2.1.1. Cephems: Cephalosporins

2.1.2. Penems: Carbapenems

2.1.3. Monobactams

2.2. Non-β-Lactam PBP Inhibitors

2.2.1. Covalent Inhibitors

2.2.2. Noncovalent Inhibitors

3. β-Lactamase Inhibitors

3.1. Serine β-Lactamase Inhibitors

3.1.1. DBO-Based BLIs

3.1.2. Boronic Acid-Based BLIs

3.2. Metallo-β-Lactamase Inhibitors

3.2.1. Dicarboxylate Inhibitors

3.2.2. Thiolate-Based Inhibitors

3.2.3. Other Small Molecule Inhibitors

4. Conclusions and Outlook

References

Section 6: Topics in Biology

Chapter Seventeen: Tumor Microenvironment as Target in Cancer Therapy

1. Introduction

2. Cancer-Promoting Enzymes and Inhibitors

2.1. MMPs and Their Inhibitors

2.1.1. Matrix Metalloproteinase-2 and Its Inhibitors

2.1.2. Matrix Metalloproteinase-12 and Its Inhibitors

2.1.3. Matrix Metalloproteinase-13 and Its Inhibitors

2.1.4. Tumor Necrosis Factor--Converting Enzyme and Its Inhibitors

2.2. Regulation of Microenvironment pH

2.2.1. H+ Pumps and Transporters

2.2.2. Tumor-Associated Carbonic Anhydrases

2.3. Ectonucleotidases

2.3.1. Autotaxin

2.3.2. CD73

2.3.3. CD39

2.3.4. Miscellaneous

3. Carbamoylphosphonates: Inhibitors of Extracellular Zinc-Enzymes

4. Conclusions and Outlook

Acknowledgments

References

Chapter Eighteen: Novel Screening Paradigms for the Identification of Allosteric Modulators and/or Biased Ligands for Cha...

1. Introduction

2. Allosteric Modulators

2.1. AM Screening: Challenges

2.2. AM Screening: Illustrative Examples

2.3. AM Screening: Novel Approaches

3. Biased Ligands

3.1. BL Identification: Characteristics

3.2. BL Identification: Illustrative Examples

3.3. BL Identification: Novel Approaches

4. Ab Discovery as Novel AMs/BLs

5. Conclusions

References

Chapter Nineteen: Mer Receptor Tyrosine Kinase: Therapeutic Opportunities in Oncology, Virology, and Cardiovascular Indic...

1. Introduction

2. Mer Biological Function and Therapeutic Opportunities

2.1. Mer´s Role in Macrophages, Natural Killer, and Dendritic Cells

2.2. Aberrant Expression of Mer in Hematological and Solid Tumors: A Dual Target for Anticancer Effects

2.3. The Role of TAM Family Kinases in Viral Immune Avoidance

2.4. Mer´s Role in Coagulation: An Anticoagulation Target with Minimal Bleeding Liabilities

3. Small Molecule Mer Inhibitors

3.1. Current Clinical Agents with TAM Family Activity

3.2. Novel Mer Inhibitors with Activity in In Vivo Models of Antitumor, Anticoagulation, and Antiviral Indications

4. Future Directions and Conclusions

References

Section 7: Topics in Drug Design and Discovery

Chapter Twenty: Disease-Modifying Agents for the Treatment of Cystic Fibrosis

1. Introduction

1.1. Classes of CFTR Mutations

1.2. Cellular Assays

1.3. Other Strategies to Correct Airway Surface Liquid Defects

2. Treating Class I Defects

2.1. Ataluren (PTC124, 1)

2.2. NB124 (2)

3. Treating Class II Defects (Correctors)

3.1. VX-809 (Lumacaftor, 3)

3.2. VX-661 (4)

3.3. FDL169

3.4. 407882 (5)

3.5. Matrine (6)

3.6. Apoptozole (7)

3.7. Latonduine A (8)

3.8. Kinase Inhibitors

3.9. Other Correctors

4. Treating Class III Defects (Potentiators)

4.1. VX-770 (Ivacaftor, 12)

4.2. RP193

4.3. GLPG1837

4.4. Other Potentiators

5. Compounds with Dual Activity

5.1. N6022 (15) and N91115

5.2. CoPo-22 (16)

5.3. Hyalout4 (17)

5.4. Other Compounds with Dual Activity

6. Conclusions

References

Chapter Twenty-One: Advancements in Stapled Peptide Drug Discovery and Development

1. Introduction

2. Beneficial Effects Attributed to the Hydrocarbon Staple

2.1. Enhancing Pharmacokinetic Properties

2.2. Generating Cell Permeability

2.3. Improved Target Affinity and Target Specificity

3. Drug Discovery: Preclinical Research

3.1. BCL-2 Pathway Modulators

3.2. Wnt Pathway Modulators

3.3. HIV Inhibitors

4. Drug Development and P53 Reactivation

4.1. From In Vitro to In Vivo Proof of Concept

4.2. Advantages with SPs over Small Molecules

5. Concluding Remarks

References

Chapter Twenty-Two: Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development

1. Introduction

2. Identification of CYP-Modified Natural Products as Drug Leads

2.1. Antineoplastic Agents

2.2. Antiprotozoal Agents

2.3. Antifungal Agents

3. Identification of Pharmacologically Active Metabolites of Known Drugs

3.1. Statin Metabolites

3.2. Antibiotics

3.3. Antidepressants

3.4. Antihistamines

3.5. Muscarinic Antagonists

3.6. Antineoplastic Agents

4. Future Directions and Conclusions

Acknowledgments

References

Section 8: Case Histories and NCEs

Chapter Twenty-Three: Case History: ForxigaTM (Dapagliflozin), a Potent Selective SGLT2 Inhibitor for Treatment of Diabetes

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

References

Chapter Twenty-Four: Case History: Kalydeco® (VX-770, Ivacaftor), a CFTR Potentiator for the Treatment of Patients with C...

1. Introduction

2. CFTR as a Drug Discovery Target

3. The Discovery of CFTR Potentiators

4. Medicinal Chemistry Efforts Culminating in Ivacaftor

4.1. Hit-to-Lead Efforts

4.2. Reducing the Planarity of VRT-715

4.3. Final Compound Selection

5. Preclinical Properties of Ivacaftor

6. Formulation Development

7. Clinical Studies

8. Conclusion

References

Chapter Twenty-Five: Case History: Xeljanz (Tofacitinib Citrate), a First-in-Class Janus Kinase Inhibitor for the Treatme...

1. Introduction

2. Rationale for Targeting the JAK Enzymes

3. Medicinal Chemistry Efforts Culminating in the Identification of Tofacitinib15

3.1. Lead Identification: High-Throughput Screening

3.2. Early Structure-Activity Relationships: Developing a Pharmacophore Model

3.3. Informing Headgroup Structure: High-Speed Analoging and Natural Products

3.4. Optimizing Property Space and ADME

4. Selectivity and Pharmacology of Tofacitinib

5. Preclinical Properties of Tofacitinib

6. Clinical Properties of Tofacitinib

7. Conclusions

Acknowledgments

References

Chapter Twenty-Six: New Chemical Entities Entering Phase III Trials in 2013

Selection Criteria

Facts and Figures

References

Chapter Twenty-Seven: To Market, To Market-2013

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

References

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)

Color Plate