Characterization QAW039 and QAV680, two novel, potent and selective CRTh2 antagonists

Introduction QAW039 is an oral, selective, competitive and reversible CRTh2 receptor antagonist. The present study aims to provide a detailed pharmacological characterisation of QAW039 and QAV680 (two potent and selective CRTh2 antagonists). Methods Antagonist properties such as potency, selectivity and functional activity of QAW039 and QAV680 were characterized through various pharmacology assays [radio ligand binding, cAMP functional assay, eosinophil shape change (ESC) and Th2 cytokine production]. Results QAW039 and QAV680 are sub-nM antagonists at the human CRTh2 receptor with an affinity (Ki) of 4.7 and 29 nM respectively. Both compounds are highly selective for CRTh2 receptors, potent inhibitors of ESC, and effectively found to inhibit PGD2- induced IL-3 and IL-5 production from human peripheral blood Th2 cells (Table). Conclusion QAW039 showed superior potency compared to QAV680 with minimal drop off in whole blood eosinophil shape change assay compared to QAV680 (1.9 vs 15-fold). The efficacy of QAW039 is currently being evaluated clinically in moderate-to-severe asthma patients.