LAUSR

Background: Inhibitors of the extracellular calcium-sensing receptor (CaSR), termed calcilytics, were developed to evoke pulsatile changes in plasma parathyroid hormone (PTH) levels as a novel anti-osteoporotic treatment. Recently we have shown that they can suppress airway hyperresponsiveness (AHR) and inflammation in asthma models, providing a potential for a novel asthma treatment strategy1. Objective: To develop a new calcilytic specifically for the treatment of airway disease and test its efficacy in allergic asthma. Methods: The efficacy of a new chemical class of calcilytics to suppress CaSR signalling was tested in vitro in human embryonic kidney 293 cells expressing the CaSR. The most active stereoisomer of one compound (B2.1-E1) was tested for its biological activity in vivo by administering the calcilytic solution to mice via gavage, after which plasma PTH levels were measured. Finally, the efficacy of the inhaled calcilytics to suppress AHR and inflammation was tested in the poly-L-arginine-induced model of AHR and the ovalbumin-sensitised acute asthma model in mice1. Results: B2.1-E1 supressed CaSR signalling in vitro and increased PTH levels in vivo. Inhaled B2.1-E1 led to dose-dependent suppression of AHR evoked by poly-L-arginine, and diminished AHR and inflammation in the acute asthma model in vivo. Conclusions: The novel calcilytic B2.1-E1 suppressed CaSR in vitro, and elicited PTH release in vivo. In addition, B2.1-E1 suppressed AHR and inflammation in mice, providing a rationale for further development of this calcilytic and its chemical class for the treatment of inflammatory lung disease (IP GB1719023.2). References:1Yarova PL et al. (2015). Science TM 7: 284ra60.