PT  - JOURNAL ARTICLE
AU  - David A Sykes
AU  - Michelle E Bradley
AU  - Darren M Riddy
AU  - Elizabeth Willard
AU  - John Reilly
AU  - Asadh Miah
AU  - Carsten Bauer
AU  - Simon J Watson
AU  - David A Sandham
AU  - Gerald Dubois
AU  - Steven J Charlton
TI  - Fevipiprant (QAW039) a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy.
AID  - 10.1124/mol.115.101832
DP  - 2016 Jan 01
TA  - Molecular Pharmacology
PG  - mol.115.101832
4099  - http://molpharm.aspetjournals.org/content/early/2016/02/25/mol.115.101832.short
4100  - http://molpharm.aspetjournals.org/content/early/2016/02/25/mol.115.101832.full
AB  - 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 kon and koff values for QAW039 of 4.5x107 M-1min-1 and 0.048 min-1 respectively. Importantly, the kinetic off-rate (koff) of QAW039 (t1/2 = 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.