QAW039, a slowly dissociating CRTh2 antagonist with potential for improved clinical efficacy

Abstract

Introduction QAW039 is an oral, selective, competitive and reversible CRTh2 receptor antagonist currently in clinical development for treatment of asthma. This study describes the detailed investigation of the receptor binding kinetics of QAW039 and compares it to several other known CRTh2 antagonists. Methods Kinetic binding experiments with [3H3]-QAW039 and CRTh2 receptor were carried out at 37oC, [35S]-GTPγS binding at room temperature1. The ability of compounds to inhibit the whole blood shape change (WBSC) response to PGD2 was monitored using flow cytometry. Results The dissociation rate constant for QAW039 was significantly lower than all other clinically relevant CRTh2 antagonists tested (QAV680, OC459 and AZD-1981, Table). QAW039 was the most potent compound tested in the WBSC assay. In the binding assay QAW039 significantly reduced the maximum effect of PGD2 following a 15min incubation. View this table: Table. Kinetic parameters and WBSC IC50 values Conclusion The slower off-rate of QAW039 from the CRTh2 receptor potentially affords it an improved efficacy, as it can insurmountably block the CRTh2 receptor even in the face of high local concentrations of PGD2. Reference 1. Sykes et al. Mol Pharm 2009; 76:543-51.