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Characterisation of negative allosteric modulators of the calcium-sensing receptor, CaSR, for repurposing as a treatment for asthma

Yarova, Polina L., Huang, Ping, Schepelmann, Martin W., Bruce, Richard, Ecker, Rupert, Nica, Robert, Telezhkin, Vsevolod S., Traini, Daniela, Gomes dos Reis, Larissa, Kidd, Emma J., Ford, William R., Broadley, Kenneth J., Kariuki, Benson M., Corrigan, Christopher J., Ward, Jeremy P. T., Kemp, Paul J. and Riccardi, Daniela 2021. Characterisation of negative allosteric modulators of the calcium-sensing receptor, CaSR, for repurposing as a treatment for asthma. Journal of Pharmacology and Experimental Therapeutics 376 (1) , pp. 51-63. 10.1124/jpet.120.000281
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Abstract

Asthma is still an incurable disease and there is a recognised need for novel small molecule therapies for people with asthma, especially those poorly controlled by current treatments. We previously demonstrated that calcium-sensing receptor negative allosteric modulators (CaSR NAMs), calcilytics, uniquely suppress both airway hyperresponsiveness (AHR) and inflammation in human cells and murine asthma surrogates. Here we assess the feasibility of repurposing four CaSR NAMs, originally developed for oral therapy for osteoporosis and previously tested in the clinic, as a novel, single and comprehensive topical anti-asthma therapy. We address the hypotheses, using murine asthma surrogates, that topically-delivered CaSR NAMs (i) abolish AHR; (ii) are unlikely to cause unwanted systemic effects; (iii) are suitable for topical application; (iv) inhibit airways inflammation to the same degree as the current standard of care, inhaled corticosteroid (ICS), and furthermore inhibit airways remodelling. All four CaSR NAMs inhibited poly-L-arginine-induced AHR in naïve mice, and suppressed both AHR and airways inflammation in a murine surrogate of acute asthma, confirming class specificity. Repeated exposure to inhaled CaSR NAMs did not alter blood pressure, heart rate or serum calcium concentrations. Optimal candidates for repurposing were identified based on anti-AHR/inflammatory activities, PK/PD, formulation and micronization studies. Whereas both inhaled CaSR NAMs and inhaled corticosteroids reduced airways inflammation, only the former prevented goblet cell hyperplasia in a chronic asthma model. We conclude that inhaled CaSR NAMs are likely a single, safe and effective topical therapy for human asthma, abolishing AHR, suppressing airways inflammation and abrogating some features of airways remodelling.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Biosciences
Publisher: American Society for Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
Date of First Compliant Deposit: 13 October 2020
Date of Acceptance: 4 October 2020
Last Modified: 16 Feb 2021 18:46
URI: http://orca.cf.ac.uk/id/eprint/135568

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