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?
The Future of GPCRs in Drug Discovery
Executive summary 10
Introduction 10
Characteristics of GPCRs 10
Commercial exploitation 11
New approaches 12
New opportunities 13
Specialist company profiles 14
Market outlook for dugs targeting GPCRs 14
Chapter 1 Introduction 18
Summary 18
Introduction 18
GPCRs in the human genome 19
Additional opportunities 20
The leading class of drug targets 21
Commercially validated targets 23
Chapter 2 Characteristics of GPCRs 28
Summary 28
Introduction 28
Protein structure 29
Functional receptors 31
Second messengers 31
Agonists, antagonists, partial agonists, and inverse agonists 33
Chapter 3 Commercial exploitation 36
Summary 36
Introduction 37
Current successes 37
Targeted GPCRs 44
Unexplored targets 47
Difficult targets 50
Opportunities 50
Chapter 4 New approaches 54
Summary 54
Introduction 55
Screening methods 56
Structure-based methods 57
Knowledge-based methods 60
Allosteric modulators 62
Bifunctional ligands 65
Dimeric receptor targeting ligands 66
Biased ligands 68
Chapter 5 New opportunities 72
Summary 72
Introduction 73
Enhanced selectivity 73
Atypical antipsychotics 75
Lorcaserin 78
Adenosine A2A antagonists 79
New targets 80
Ghrelin antagonists 81
GPR119 agonists 81
H4 antagonists 82
DP2 antagonists 82
GPR109A agonists 83
GPBA agonists 84
New indications 85
Diabetes 85
Obesity 86
Osteoporosis 86
COPD 87
Alzheimer’s disease 87
Chapter 6 Specialist company profiles 92
Summary 92
Introduction 92
7TM Pharma 93
Actelion 94
Acure Pharma 95
Addex Pharmaceuticals 95
Arena Pharmaceuticals 97
Ascent Therapeutics 98
Cara Therapeutics 99
Compugen 99
Dimerix Bioscience 100
DiscoveRx 100
Domain Therapeutics 100
Euroscreen 101
Galapagos 102
Heptahelix 103
Heptares Therapeutics 103
Oxagen 104
Prosarix 104
Tranzyme Pharma 105
Trevena 105
Chapter 7 Market outlook for drugs targeting GPCRs 108
Summary 108
Sustained opportunities 108
Exploited GPCRs 109
Unexploited GPCRs 110
Orphan GPCRs 111
Current treatments 111
Upcoming treatments 114
Overall assessment 117
Appendix 119
Bibliography 119
Glossary 126
Index 129
List of Figures
Figure 1.1: Commercially exploited targets by target type 22
Figure 1.2: Exploited and unexploited GPCRs by class 23
Figure 2.3: Heptahelical structure of Class A and Class B GPCRs 29
Figure 2.4: Schematic diagram of Class C GPCRs 30
Figure 2.5: GPCR signaling 32
Figure 2.6: Schematic dose response curves to different types of GPCR ligand 33
Figure 3.7: Exploitation of class A GPCRs 38
Figure 3.8: Schematic phylogenetic relationship between groups of Class A GPCRs 45
Figure 3.9: Relative exploration of groups of class A GPCRs 49
Figure 4.10: Strategic opportunities in targeting GPCRs 55
Figure 4.11: Timeline of GPCR 3-dimensional structural information 58
Figure 4.12: Potential advantages with allosteric modulators of GPCR function 62
Figure 4.13: Schematic of allosteric modulator approach 63
Figure 4.14: Comparison of biased ligands and conventional GPCR ligands 69
Figure 5.15: Approach to more selective antipsychotic drugs 76
Figure 5.16: Lorcaserin, enhanced 5-HT2C receptor selectivity 78
Figure 7.17: Continued opportunities to exploit GPCRs 109
Figure 7.18: Angiotensin AT1 antagonists - the patent cliff in the US 113
List of Tables
Table 1.1: Classes of GPCRs 19
Table 1.2: Sales of GPCR-directed drugs achieving sales of >$250m in 2009 24
Table 3.3: Sales of AT1 receptor antagonists ($m), 2009 42
Table 5.4: GPR119 agonists in development for the treatment of type 2 diabetes 82
Table 5.5: DP2 antagonists in development for the treatment of asthma 83
Table 6.6: GPCR pipeline of 7TM Pharma 93
Table 6.7: GPCR pipeline of Actelion 94
Table 6.8: GPCR pipeline of Addex Pharmaceuticals 96
Table 6.9: GPCR pipeline of Arena Pharmaceuticals 97
Table 6.10: GPCR pipeline of Domain Therapeutics 101
Table 6.11: GPCR pipeline of Euroscreen 102
Table 6.12: GPCR pipeline of Tranzyme Pharma 105
Table 7.13: Drugs in advanced development, targeting unexploited GPCRs 115
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