GPCRs: Dawn of a New Era?

Publication Date	October 2008
Publisher	Insight Pharma Reports
Product Type	Report
Pages	192
ISBN Number	not applicable
Product Code	IPR00010

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Summary

Current advances in functional screening methodologies, medicinal chemistry, and structure-based drug design have generated large increases in the number and diversity of GPCR drug targets. Furthermore, basic research advances have opened the way for still further exploitation of this target class. This report:

Explores current and likely consequences of recent advances concerning GPCR x-ray structures, allosteric interactions, multimerization, and functional selectivity;
Extensively tabulates marketed drugs and compounds in development arranged by receptor type and subtype;
Presents in-depth interviews with recognized experts in the field.

G protein-coupled receptors (GPCRs) are popular drug targets, accounting for about one-third of approved drugs and many hundreds of drugs currently in development. Yet one can easily argue that the pharmacologic potential of GPCRs is far from exhausted. Currently approved drugs address only a few GPCRs. Technologic and scientific advances have resulted in R&D pipelines that target a great many more GPCRs than are represented among currently marketed products. In this report, we examine newer technologies used in GPCR pharmacology.

Furthermore, the evolution of GPCR pharmacology is far from over. Basic researchers have made a number of exciting and relevant discoveries in the past decade, and these have already begun to make important contributions to drug discovery. GPCRs: Dawn of a New Era? examines the current state of basic research, featuring key developments with the potential to favorably impact future drug discovery.

We consider the exciting area of allosteric modulation, which has already yielded two marketed drugs and promises many more, some with capabilities heretofore inaccessible. We also examine two other areas in basic research that promise to have significant impact on the field: functional selectivity and the role of homo- and heterodimers in GPCR function.
Another basic research advance, described herein, has, arguably, the greatest potential for advancing GPCR pharmacology. Until this year, drug discovery scientists had available to them only a single high-resolution x-ray crystallographic structure of a GPCR. That was for rhodopsin, which is atypical from the drug discovery perspective. Two relevant structures have become available, thus energizing the GPCR structure-based drug design community.

GPCRs: Dawn of a New Era? then examines trends in applied GPCR research before turning to a thorough presentation and analysis of marketed GPCR-based drugs and of compounds currently in development or registration. We consider all GPCR types and subtypes that are the subject of approved drugs or pipeline candidates.
The report spotlights numerous small pharmaceutical companies, which tend to push the limits of GPCR pharmacology by attacking more targets and by attempting to apply cutting-edge concepts derived from basic research. In addition, we present a compendium of views on a variety of relevant findings and issues in the field based on our extensive discussions with GPCR experts.

About the author:
Ken Rubenstein, PhD, a biochemist and molecular biologist, received his PhD at the University of Wisconsin and postdoctoral training at the University of Pennsylvania School of Medicine. He was a key innovator and research manager for Syva Company, the diagnostics branch of Syntex Corporation. During his 13 years with Syva, Dr. Rubenstein became vice president, scientific affairs, a function that included strategic planning. Since 1983, he has served as a technology and marketing consultant to biomedical companies and an industry analyst, with more than 40 published studies to his credit.

Content

Chapter 1
Introduction: The Untapped Pharmacologic Potential of Gpcrs
- 1.1. Research Advances Stimulating Gpcr-Based Drug Discovery
- 1.2. Goals and Organization of Report
Chapter 2
Scientific Background and Technologies
- 2.1. Nature of Gpcrs
- Gpcrs as Drug Targets
- Gpcr Classification
- 2.2. Compound Selection
- Functional Assays for Gpcr Signaling
- Calcium Assays
- Cellular Dielectric Spectroscopy
- Beta-Arrestin Assays
- Structure-Based Drug Discovery
Chapter 3
Gpcr Pharmacology: Key Advances in Basic Research
- 3.1. Significance of Gpcr Structures
- X-Ray Crystallographic Structure of The Beta2-Adrenergic Receptor...solved
- Implications for Structure-Based Drug Design for Gpcrs
- 3.2. Deorphanization
- 3.3. Allosteric Modulators
- 3.4. Dimers and Oligomers
- 3.5. Functional Selectivity
Chapter 4
Applied Research
- 4.1. Small Companies Push The Limits of Gpcr Pharmacology
- 7tm Pharma
- Acadia Pharmaceuticals
- Actelion
- Acurepharma
- Addex Pharmaceuticals
- Adenosine Therapeutics (Acquired by Clinical Data)
- Arena Pharmaceuticals
- Cara Therapeutics
- Dimerix Bioscience
- Epix Pharmaceuticals
- Trevena
- 4.2. The Gpcr Pipeline
- Serotonin Receptors
- 5-Ht1 Receptor
- 5-Ht2 Receptor
- 5-Ht4 to 5-Ht7 Receptors
- Adenosine Receptors
- A1 Receptor
- A2 and A3 Receptors
- Adrenergic Receptors
- Alpha Adrenergic Receptor
- Beta Adrenergic Receptor
- Angiotensin Ii Receptor
- Arginine Vasopressin Receptor
- Bradykinin Receptors
- Calcitonin Receptors
- Cannabinoid Receptor
- Chemokine Receptors
- Cholecystokinin Receptor
- Muscarinic Acetylcholine Receptor
- Coagulation Factor Ii Receptor
- Corticotropin-Releasing Hormone Receptor 1
- Dopamine Receptors
- Endothelin Receptor Type A
- Gabab Receptor
- Glucagon Receptor Family
- Metabotropic Glutamate Receptors
- Gonadotropin-Releasing Hormone Receptor
- Ghrelin Receptor
- Histamine Receptor
- Interleukin 8 Receptor
- Melanin-Concentrating Hormone Receptor 1
- Melanocortin Receptor
- Motilin Receptor
- Opiate Receptor-like 1 and Opioid Receptors
- Oxytocin Receptor
- Prostaglandin Receptors
- Gpcr44
- Purinergic P2y Receptors
- Sphingosine-1-Phosphate Receptor 1
- Tachykinin Receptors
- Additional Gpcr Modulators
Chapter 5
- Deals, Observations, and Conclusions
- 5.1. Selected Gpcr-Related Deals
- 5.2. Strengths and Weaknesses of Gpcrs as A Target Class
- Strengths
- Weaknesses
- 5.3. General Observations and Findings
- Diversity of Gpcrs for Drug Discovery and Development
- Translation of Basic Research and New Technologies
- Functional Versus Ligand-Binding Screening Assays
- Cell Impedance Screening Technology
- Role of Allostery in Drug Discovery and Development
- Role of Dimers and Oligomers in Drug Discovery and Development
- Relationship of Signaling Pathway to Disease
- Deorphanization and Unfamiliar Gpcrs
- Structure-Based Drug Design
- 5.4. Conclusions
Chapter 6
Expert Interviews
- 6.1. Annette Gilchrist, Phd
- Adjunct Professor; Northwestern University
- 6.2. Graeme Milligan, Phd
- Professor of Molecular Pharmacology; Joint Research Director, Faculty of Biomedical and Life Sciences; University of Glasgow
- 6.3. Anonymous
- Screening and Profiling Director; Major Pharmaceutical Company X
- 6.4. P. Jeffrey Conn, Phd
- Lee E. Limbird Professor of Pharmacology; Director, Vanderbilt Program in Drug Discovery; Vanderbilt University Medical Center
- 6.5. Sidney Topiol, Phd
- Associate Director, Computational Chemistry; Lundbeck Research
- 6.6. Vincent Mutel, Phd
- Ceo, Vice Chairman, and Co-Founder; Addex Pharmaceuticals
- References
- Company Index with Web Addresses
Figures
- Figure 2.1. Diagram of A Flipr Instrument and Typical Kinetic Tracings
- Figure 2.2. Crystal Structure of The Beta2-Adrenergic Receptor Protein
- Tables
- Table 2.1. Major Gpcr Subclasses
- Table 4.1. Launched Drugs Targeting Serotonin 1 Receptors
- Table 4.2. Drug Candidates for Serotonin 1 Receptors
- Table 4.3. Launched Drugs Targeting Serotonin 2 Receptors
- Table 4.4. Drug Candidates for Serotonin 2 Receptors
- Table 4.5. Launched Drugs Targeting Serotonin 4 Receptors
- Table 4.6. Drug Candidates for Serotonin 4 Receptors
- Table 4.7. Drug Candidates for Serotonin 5, 6, and 7 Receptors
- Table 4.8. Drug Candidates for Adenosine A1 Receptors
- Table 4.9. Drug Candidates for Adenosine A2 and A3 Receptors
- Table 4.10. Launched Drugs Targeting Alpha Adrenergic Receptors
- Table 4.11. Drug Candidates for Alpha Adrenergic Receptors
- Table 4.12. Launched Drugs Targeting Beta-1 Adrenergic Receptors
- Table 4.13. Drug Candidates for Beta-1 Adrenergic Receptors
- Table 4.14. Launched Drugs Targeting Beta-2 Adrenergic Receptors
- Table 4.15. Drug Candidates for Beta-2 Adrenergic Receptors
- Table 4.16. Drug Candidates for Beta-3 Adrenergic Receptors
- Table 4.17. Launched Drugs Targeting Angiotensin Ii Receptor, Type 1
- Table 4.18. Drug Candidates for Arginine Vasopressin Receptors
- Table 4.19. Drug Candidates for Bradykinin Receptors
- Table 4.20. Drug Candidates for Calcitonin and Calcitonin-like Receptors
- Table 4.21. Preclinical Drug Candidates for Cannabinoid 1 Receptors
- Table 4.22. Clinical Drug Candidates for Cannabinoid 1 Receptors
- Table 4.23. Drug Candidates for Cannabinoid 2 Receptors
- Table 4.24. Drug Candidates for Chemokine Receptors
- Table 4.25. Drug Candidates for Cholecystokinin Receptors
- Table 4.26. Launched Drugs Targeting Muscarinic Receptor 1
- Table 4.27. Drug Candidates for Muscarinic 1 and 2 Cholinergic Receptors
- Table 4.28. Launched Drugs Targeting Muscarinic Receptor 3
- Table 4.29. Drug Candidates for Muscarinic 3 Cholinergic Receptors
- Table 4.30. Drug Candidates for Coagulation Factor Ii Receptor
- Table 4.31. Drug Candidates for Corticotropin-Releasing Hormone Receptors
- Table 4.32. Launched Drugs Targeting The Dopamine D2 Receptor
- Table 4.33. Drug Candidates for Dopamine Receptors
- Table 4.34. Drug Candidates for Endothelin Receptor Type A
- Table 4.35. Drug Candidates for Gabab Receptors
- Table 4.36. Drug Candidates for Glucagon and Glucagon-like Peptide-1 Receptors
- Table 4.37. Drug Candidates for Metabotropic Glutamate Receptors
- Table 4.38. Launched Drugs Targeting The Gonadotropin-Releasing Hormone Receptor
- Table 4.39. Drug Candidates for The Gonadotropin-Releasing Hormone Receptor
- Table 4.40. Drug Candidates for Ghrelin (Aka Growth Hormone Secretagogue) Receptors
- Table 4.41. Launched Drugs Targeting The Histamine H1 and H2 Receptors
- Table 4.42. Drug Candidates for Histamine Receptors
- Table 4.43. Drug Candidates for Interleukin 8 Receptors
- Table 4.44. Drug Candidates for Melanin-Concentrating Hormone Receptor 1
- Table 4.45. Drug Candidates for Melanocortin Receptors
- Table 4.46. Drug Candidates for The Motilin Receptor
- Table 4.47. Drug Candidates for Opiate Receptor-like 1; Also for Delta 1 and Kappa 1 Opioid Receptors
- Table 4.48. Drug Candidates for Opioid Receptors Mu and Sigma
- Table 4.49. Drug Candidates for The Oxytocin Receptor
- Table 4.50. Launched Drugs Targeting Prostaglandin Receptors
- Table 4.51. Drug Candidates for Prostaglandin Receptors
- Table 4.52. Drug Candidates for Gpcr 44
- Table 4.53. Drug Candidates for Purinergic Receptors
- Table 4.54. Drug Candidates for Sphingosine-1-Phosphate Receptor 1
- Table 4.55. Drug Candidates for Tachykinin Receptors
- Table 4.56. Launched Drugs Targeting Miscellaneous Gpcrs
- Table 4.57. Miscellaneous Gpcr-Targeted Drugs in Development
- Table 5.1. Selected Recent Gpcr Candidate-compound-Related Deals