Development of a new calcilytic for the treatment of inflammatory lung disease

Abstract

<b>Background:</b> 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 strategy<i>¹.</i> <b>Objective:</b> To develop a new calcilytic specifically for the treatment of airway disease and test its efficacy in allergic asthma. <b>Methods:</b> The efficacy of a new chemical class of calcilytics to suppress CaSR signalling was tested <i>in vitro</i> 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 <i>in vivo</i> 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 mice^<i>1</i>. <b>Results:</b> B2.1-E1 supressed CaSR signalling in vitro and increased PTH levels <i>in vivo</i>. 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 <i>in vivo</i>. <b>Conclusions:</b> The novel calcilytic B2.1-E1 suppressed CaSR <i>in vitro</i>, and elicited PTH release <i>in vivo</i>. 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). <b>