Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response. Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.

Here we describe the pharmacological properties of a series of clinically relevant chemoattractant receptor-homologous molecule expressed on T-helper type 2 (CRTh2) receptor antagonists including fevipiprant (NVP-QAW039 or QAW039) which is currently in development for treatment of allergic diseases. [³H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in CHO-cells, the binding being reversible and competitive with the native agonist PGD₂. The binding kinetics of QAW039 determined directly using [³H]-QAW039 revealed mean kinetic k_on and k_off values for QAW039 of 4.5x10⁷ M^-1min^-1 and 0.048 min^-1 respectively. Importantly, the kinetic off-rate (k_off) of QAW039 (t_1/2 = 14.4 min) was >7 fold slower than the slowest reference compound tested AZD-1981. In functional studies QAW039 behaved as an insurmountable antagonist of PGD₂ stimulated [³⁵S]-GTPγS activation and its effects were not fully reversed by increasing concentrations of PGD₂ following an initial 15min incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast the inhibitory effect of the other ligands tested was fully reversed by the 15 min time point, whereas QAW039's effects persisted for >180 min. All CRTh2 antagonists tested inhibited PGD₂ stimulated human eosinophil shape change but importantly QAW039 retained its potency in the whole blood shape change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off-rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD₂ induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathological PGD₂ concentrations, which may be clinically relevant.

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