The Future of GPCRs in Drug Discovery: Novel technologies, leading companies, and opportunities for target expansion
NEW YORK, Oct. 31, 2011 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:
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G-Protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors, and the pharmaceutical industry has targeted them to a greater extent than any other protein class. Despite the high revenues generated by branded drugs that are active at GPCRs, only a small fraction of the GPCR family has thus far been commercially exploited. Consequently, considerable scope exists for broadening the reach of drug discovery efforts to counteract the impending patent expiries of many of the best-selling GPCR-targeted drugs.
This report provides insight into how recent advances in the understanding of GPCR function are opening up new avenues for exploration, where the most promising opportunities lie, and which companies are best placed to advance their GPCR-based proprietary drug discovery technologies. The report begins with outlines of the current commercial status of drugs targeting GPCRs and the scientific basis of their action, offering an understanding of why the large majority of the receptor family has remained unexploited.
This is followed by discussion of the scientific developments enabling the pursuit of new approaches such as allosteric modulation, bifunctional ligand design, and the targeting of dimeric receptors. Both old and new targets are considered in terms of their potential to offer fresh opportunities, and particular attention is given to the current and future roles of orphan receptors. Finally, the report profiles a range of companies specializing in aspects of GPCR drug discovery, and the market outlook is summarized.
List of Tables
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
Companies mentioned
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Nicolas Bombourg
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