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, target residence time 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 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 H4R antagonist program and a drug development program in which compounds that simultaneously target the H1R and H4R are being developed.

• Selective Histamine H4 receptor antagonists
• Dual-action H1/H4 receptor antagonists

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, allergic rhinitis or ocular allergy). Griffin Discoveries has recently established a compelling proof of principle with the use of its dual-action H1R/H4R antagonists in a mouse model for ocular allergy.

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
– Bongers et al. (2007) J. Pharmacol. Exp. Ther. 323:888-98

Histamine H4 receptor
– Andaloussi et al. (2013) Bioorg. Med. Chem. Lett. 23:2663-70
– Smits et al. (2009) Drug Discov. Today 14;745-53
– Smits et al. (2008) J. Med. Chem. 51;2457-67
– 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