Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

作者：Sykes David A; Bradley Michelle E; Riddy Darren M; Willard Elizabeth; Reilly John; Miah Asadh; Bauer Carsten; Watson Simon J; Sandham David A^*; Dubois Gerald; Charlton Steven J^*

来源：Molecular Pharmacology, 2016, 89(5): 593-605.

DOI：10.1124/mol.115.101832

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [H-3]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 +/- 6 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D-2 (PGD(2)). The binding kinetics of QAW039 determined directly using [H-3]-QAW039 revealed mean kinetic on (k(on)) and off (k(off)) values for QAW039 of 4.5 x 10(7) M-1 min(-1) and 0.048 minute(-1), respectively. Importantly, the k(off) of QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD(2)-stimulated [S-35]-GTP gamma S activation, and its effects were not fully reversed by increasing concentrations of PGD2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for. 180 minutes. All CRTh2 antagonists tested inhibited PGD(2)-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 PGD(2)-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD(2) concentrations, which may be clinically relevant.

• 出版日期2016-5