Understand how new opportunities in the GPCR field are not confined to underexploited or orphan GPCRs.
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- Rudolph Williams
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1 Future of GPCRs in Drug Discovery: Novel Technologies, Leading Companies, and Opportunities for Target Expansion GPCRs are being actively pursued as a target class for developing new therapeutics for various indications. This report discusses the developments in targeting selected, recently deorphaned GPCRs. Scope Analysis of specific GPCRs that have been exploited or explored. Novel approaches to targeting GPCRs and their benefits, such as selectively modulating distinct GPCR signaling pathways. Case histories highlighting how enhanced selectivity can be achieved by exploiting improved knowledge of GPCR targets. Potential GPCR targets for major under-treated diseases. Commercial outlook for drugs targeting GPCRs. Assessment of the level of activity in GPCR research. Research and analysis highlights 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 The vast majority (about 80%) of GPCRs have yet to be effectively or commercially exploited, for a variety of reasons, thus offering many opportunities. Successful pursuit of such approaches, together with effective targeting of currently unexploited GPCRs, is critical to compensating for the loss of revenues as patent expirations impact upon the sales of leading branded GPCR-targeted drugs. Key reasons to purchase this research Understand how new opportunities in the GPCR field are not confined to underexploited or orphan GPCRs.
2 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. Gain insight into the predicted development of the market in GPCR therapeutics.
3 Table of Contents 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
4 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
5 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 >$250m in Table 3.3: Sales of AT1 receptor antagonists ($m), 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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