Sandham, David, Bauer, Carsten, Charlton, Steven, Sykes, David, Dubois, Gerald, Bradley, Michelle, Miah, Asadh, Riddy, Darren, Willard, Elizabeth and Watson, Simon (2016) Fevipiprant (QAW039) a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy. Molecular Pharmacology.

Abstract

Here we describe the pharmacological properties of a series of clinically relevant CRTh2 antagonists including fevipiprant (QAW039) which is currently in development for treatment of allergic diseases. Equilibrium and kinetic binding properties were studied in assay buffer containing physiological sodium ion concentration at 37oC. In saturation binding experiments [3H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in CHO-cells. Binding was selective, 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, producing a kinetic Kd value of 1.06 ± 0.06 nM which is in excellent agreement with the equilibrium Kd value obtained in the saturation binding experiments. 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 in salt containing buffer QAW039 behaved as an insurmountable antagonist of PGD2 stimulated [35S]-GTPS activation under the experimental conditions employed and was not fully displaced by increasing concentrations of PGD2 following a 15min incubation period. This behaviour is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast the inhibitory effect of other ligands tested were fully reversed by the 15 min time point whereas QAW039 inhibitory effects persisted for >180 min. Binding and functional studies were entirely consistent with a competitive mode of action with the endogenous agonist PGD2.
All CRTh2 antagonists tested inhibited PGD2 stimulated human eosinophil shape change although importantly QAW039 retained its potency in the whole blood shape change assay relative to the isolated shape change assay which may be 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. The slower CRTh2 receptor dissociation could provide increased receptor coverage in the face of pathological PGD2 concentrations, which may be clinically relevant.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25694