Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

Abstract

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

Keywords: 13,14-dihydro-15-keto-PGD(2); 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine; Allergy; BAL; BEMP; CC chemokine receptor 3; CCR-3; CRTh2; CRTh2 receptor antagonist; DK-PGD(2); ELSD; FITC; GLP; PGD(2); SC; bronchoalveolar lavage; chemoattractant receptor homologous expressed on Th2 cells; evaporative light scattering detection; fluorescein isothiocyanate; good laboratory practice; prostaglandin D(2); shape change.