GPCR Drug Discovery
With about 1000 members, G-protein coupled receptors (GPCRs) comprise the largest family of cell surface receptors. Approximately 30% of the drugs currently on the market target GPCRs while generating annual revenues of over 40 billion US dollars. These therapeutic successes together with the large number of GPCRs that are yet to be exploited as drug targets, fuel the ongoing search for new ligands. Currently many drugs that target GPCRs are in development, illustrating that the therapeutic potential of GPCR ligands is far from exhausted.

Novel concepts that have emerged from basic research such as allosteric modulation and receptor dimerization offer a number of new and exciting ways to modulate GPCR pharmacology. Drug discovery efforts that have recently led to the introduction of the first allosteric modulators to the market now reveal the promise held by these previously unexplored modes of ligand action. The recent advances in GPCR structural biology as a result of recent X-ray studies of several family A GPCRs, has revitalized GPCR structure-based drug discovery. The abundant number of untargeted GPCRs and the recent developments in basic science hold great promise for the development of new ligands and new GPCR-targeting drugs are likely to reach the market in the coming years.

R & D Focus
Current in-house discovery is comprised of a selective histamine H3R antagonist and histamine H4R antagonist program. In addition to the development of selective antagonists, a series of compounds is being developed with a mixed histaminergic profile that combines histamine H1R and histamine H4R antagonism in a single non-imidazole molecule.

• Selective Histamine H3 receptor antagonists
• Selective Histamine H4 receptor antagonists
• Dual action H1/H4 receptor antagonists
• Histaminergic ligands with a mixed profile

Some histamine-induced events are mediated by multiple histamine receptor subtypes and in some diseases this may offer new treatment paradigms with antagonists that have affinity for more than one histamine receptor subtype. It provides an exciting opportunity for the development of compounds with enhanced clinical efficacy when compared to a single receptor selective histaminergic antagonist. Compounds that display potent antagonism at both the histamine H4 and histamine H1 receptors can have an additive effect in the treatment of a single symptom (e.g. pruritis) or may be used for treating multiple histamine-induced symptoms of a single disease (e.g. allergic rhinitis).

Key contributions by Griffin scientists to the field

Histamine H1 receptor
- de Graaf et al. (2011), J. Med. Chem. 54;8195-206.

Histamine H3 receptor
- Wijtmans et al. (2008), J. Med. Chem. 51;2944-53.
- Celanire et al. (2005), Drug Discov. Today 10 ;1612-27.
- Leurs et al. (2005) Nat. Rev. Drug Discov. 4;107-20.
- de Esch et al. (2001) J. Med. Chem. 44:1666-74.
- Bongers et al. (2007) J. Pharmacol. Exp. Ther. 323:888-98.

Histamine H4 receptor
- Smits et al. (2009) Drug Discov. Today 14;745-53.
- Smits et al. (2008) J. Med. Chem. 51;2457-67.
- Smits et al. (2008) J. Med. Chem. 51;7855-65.
- Lim et al. (2009) Br. J. Pharmacol. 157;34-43.
- Lim et al. (2005) J. Pharmacol. Exp. Ther. 314;1310-21.
- Jongejan et al. (2008) J. Chem. Inf. Mod. 48;1455-63.

GPCRs
- Jongejan et al. (2005) Nat. Chem. Biol. 73;94-103.
- Ratnala et al. (2007) J. Am. Chem. Soc. 129:867-72.