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시장보고서
GPCRs: Dawn of a New Era?
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Abstract
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.
Table of Contents
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
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