Overview:
G-protein coupled receptors (GPCRs) constitute the largest, most ubiquitous, and most versatile family of membrane receptors. They also constitute the class of targets that has been most effectively exploited by the pharmaceutical industry, with approximately 30% of all currently marketed drugs acting on one or more GPCRs. Despite this, there are many GPCRs that have yet to be effectively exploited, for a variety of reasons. A number of new approaches to GPCRs are being explored that should lead to a much wider, and more effective, exploitation of this class of targets and thus provide sustained commercial success from these new developments.
Major opportunities are not solely offered by successfully targeting unexploited targets. Improved knowledge of GPCR structure and function has opened up many more opportunities for more effectively targeting exploited receptors. Better knowledge of the 3-dimensional structure of receptors, of receptor signalling pathways, and of alternative binding sites on receptors all offer new opportunities for the development of improved drugs. Such drugs may have better absolute selectivity or they may selectively modulate some aspects of receptor function.
The benefits of each strategic approach are explored, and the role of specialist companies in their exploitation is highlighted. These specialist companies provide major companies with opportunities to develop new strategic partnerships and licensing opportunities to reinforce their pipelines.
Key features of this report
• Analysis of which classes of GPCR and which specific GPCRs have been exploited or explored.
• Examination of novel approaches to targeting GPCRs and discussion of their benefits, such as exploiting X-ray structural data, targeting allosteric sites, and selectively modulating distinct GPCR signaling pathways.
• Case histories highlighting how enhanced selectivity can be achieved by exploiting improved knowledge of GPCR targets.
• Discussion of developments in targeting selected, recently deorphaned GPCRs.
Scope of this report
• Understand how new opportunities in the GPCR field are not confined to underexploited or orphan GPCRs.
• Gain awareness of the multiplicity of opportunities that are, or will become, available as knowledge of specific GPCRs improves.
• Understand which specialist companies offer technologies that would make them most relevant as potential partners.
• Identify which new approaches might be most relevant to specific project goals.
Key Market Issues
• Commercial success in exploiting GPCRs has been almost exclusively confined to a minor fraction (approximately 30%) of the 184 non-orphan class A GPCRs, primarily to the receptors activated by monoamines.
• The pharmaceutical industry still views the GPCR class of targets as offering considerable opportunities for commercial exploitation.
• There is a considerable need for new and improved treatments for metabolic diseases, especially diabetes, many CNS disorders, and some inflammatory and autoimmune diseases such as COPD and multiple sclerosis. Targeting specific GPCRs for the treatment of these conditions remains an attractive option because of the druggability of this class of targets.
Key findings from this report
• The pharmaceutical industry has more effectively exploited GPCRs than it has any other target class, with GPCRs accounting for about 30% of exploited targets and revenues of over $60 billion in 2009.
• The vast majority (about 80%) of GPCRs have yet to be effectively or commercially exploited, for a variety of reasons, thus offering many opportunities.
• Alternative methods of modulating GPCR function considerably amplify the number of potential opportunities with respect to both target and strategy, and they also enhance the prospects of obtaining secure intellectual property.
• Specialist companies are leading the field in the exploitation of new approaches to the modulation of GPCR activity.
Key questions answered
1. Which GPCRs have been successfully exploited?
2. Which other GPCRs are currently viewed as desirable targets for exploitation?
3. Which recently deorphaned GPCRs have stimulated significant R&D activity?
4. Which targets are currently attracting the most attention?
5. Do opportunities remain for pursuing GPCRs which have already been commercially exploited?
6. Which targets are being pursued using new approaches to the selective modulation of GPCR function?
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Table Of Contents :
The Future of GPCRs in Drug Discovery
Executive summary
Introduction
Characteristics of GPCRs
Commercial exploitation
New approaches
New opportunities
Specialist company profiles
Market outlook for dugs targeting GPCRs
Chapter 1 Introduction
Summary
Introduction
GPCRs in the human genome
Additional opportunities
The leading class of drug targets
Commercially validated targets
Chapter 2 Characteristics of GPCRs
Summary
Introduction
Protein structure
Functional receptors
Second messengers
Agonists, antagonists, partial agonists, and inverse agonists
Chapter 3 Commercial exploitation
Summary
Introduction
Current successes
Targeted GPCRs
Unexplored targets
Difficult targets
Opportunities
Chapter 4 New approaches
Summary
Introduction
Screening methods
Structure-based methods
Knowledge-based methods
Allosteric modulators
Bifunctional ligands
Dimeric receptor targeting ligands
Biased ligands
Chapter 5 New opportunities
Summary
Introduction
Enhanced selectivity
Atypical antipsychotics
Lorcaserin
Adenosine A2A antagonists
New targets
Ghrelin antagonists
GPR119 agonists
H4 antagonists
DP2 antagonists
GPR109A agonists
GPBA agonists
New indications
Diabetes
Obesity
Osteoporosis
COPD
Alzheimer’s disease
Chapter 6 Specialist company profiles
Summary
Introduction
7TM Pharma
Actelion
Acure Pharma
Addex Pharmaceuticals
Arena Pharmaceuticals
Ascent Therapeutics
Cara Therapeutics
Compugen
Dimerix Bioscience
DiscoveRx
Domain Therapeutics
Euroscreen
Galapagos
Heptahelix
Heptares Therapeutics
Oxagen
Prosarix
Tranzyme Pharma
Trevena
Chapter 7 Market outlook for drugs targeting GPCRs
Summary
Sustained opportunities
Exploited GPCRs
Unexploited GPCRs
Orphan GPCRs
Current treatments
Upcoming treatments
Overall assessment
Appendix
Bibliography
Glossary
Index
List of Figures
Figure 1.1: Commercially exploited targets by target type
Figure 1.2: Exploited and unexploited GPCRs by class
Figure 2.3: Heptahelical structure of Class A and Class B GPCRs
Figure 2.4: Schematic diagram of Class C GPCRs
Figure 2.5: GPCR signaling
Figure 2.6: Schematic dose response curves to different types of GPCR ligand
Figure 3.7: Exploitation of class A GPCRs
Figure 3.8: Schematic phylogenetic relationship between groups of Class A GPCRs
Figure 3.9: Relative exploration of groups of class A GPCRs
Figure 4.10: Strategic opportunities in targeting GPCRs
Figure 4.11: Timeline of GPCR 3-dimensional structural information
Figure 4.12: Potential advantages with allosteric modulators of GPCR function
Figure 4.13: Schematic of allosteric modulator approach
Figure 4.14: Comparison of biased ligands and conventional GPCR ligands
Figure 5.15: Approach to more selective antipsychotic drugs
Figure 5.16: Lorcaserin, enhanced 5-HT2C receptor selectivity
Figure 7.17: Continued opportunities to exploit GPCRs
Figure 7.18: Angiotensin AT1 antagonists - the patent cliff in the US
List of Tables
Table 1.1: Classes of GPCRs
Table 1.2: Sales of GPCR-directed drugs achieving sales of >$250m in 2009
Table 3.3: Sales of AT1 receptor antagonists ($m), 2009
Table 5.4: GPR119 agonists in development for the treatment of type 2 diabetes
Table 5.5: DP2 antagonists in development for the treatment of asthma
Table 6.6: GPCR pipeline of 7TM Pharma
Table 6.7: GPCR pipeline of Actelion
Table 6.8: GPCR pipeline of Addex Pharmaceuticals
Table 6.9: GPCR pipeline of Arena Pharmaceuticals
Table 6.10: GPCR pipeline of Domain Therapeutics
Table 6.11: GPCR pipeline of Euroscreen
Table 6.12: GPCR pipeline of Tranzyme Pharma
Table 7.13: Drugs in advanced development, targeting unexploited GPCRs
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