Abstract
Introduction: Calcium release activated calcium channels inhibitors have a potent role in treatment of autoimmune disorders mediated dysregulated T-lymphocyte and mast cell functioning. Herein, we describe the pre-clinical of RP3128, a novel and potent CRAC channel inhibitor with scope for development as a clinical candidate for asthma.
Methods: Inhibition of CRAC channel activity in Jurkat cells, cytokine release from human whole blood or PBMC, and mast cell degranulation were estimated. In vivo efficacy of the compound was determined in experimental models of asthma in guinea pigs including PAF or ovalbumin induced eosinophil infiltration into lungs as well as ovalbumin induced histamine release from mast cells.
Results: RP3128 significantly inhibited calcium entry into Jurkat cells (33 nM) besides reducing IL-4 (<250 nM) and IL-5 (<50 nM) release from human whole blood and PBMC. Additionally, the compound suppressed IgE-induced mast cell degranulation at low nanomolar concentrations. Guinea pigs treated with low doses (1-3 mg/kg/po) of RP3128 displayed >70% reduction in eosinophil infiltration in an acute model of PAF-induced allergic asthma as well as in an experimental model of ovalbumin-induced chronic airway inflammation. Consistent with in vitro findings, the compound caused a significant inhibition of mast cell degranulation manifested by a reduction in histamine release.
Conclusions: Results demonstrate the potential of RP3128 as an antiasthmatic agent as evidenced from pre-clinical data. Further biological profiling in respiratory models is planned in addition to toxicological evaluation prior to Phase 1 clinical trials.
- © 2011 ERS