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Research ArticleDrug Discovery and Translational Medicine

Characterization of Negative Allosteric Modulators of the Calcium-Sensing Receptor for Repurposing as a Treatment of Asthma

Polina L. Yarova, Ping Huang, Martin W. Schepelmann, Richard Bruce, Rupert Ecker, Robert Nica, Vsevolod Telezhkin, Daniela Traini, Larissa Gomes dos Reis, Emma J. Kidd, William R. Ford, Kenneth J. Broadley, Benson M. Kariuki, Christopher J. Corrigan, Jeremy P.T. Ward, Paul J. Kemp and Daniela Riccardi
Journal of Pharmacology and Experimental Therapeutics January 2021, 376 (1) 51-63; DOI: https://doi.org/10.1124/jpet.120.000281
Polina L. Yarova
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Ping Huang
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Martin W. Schepelmann
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Richard Bruce
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Rupert Ecker
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Robert Nica
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Vsevolod Telezhkin
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Daniela Traini
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Larissa Gomes dos Reis
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Emma J. Kidd
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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William R. Ford
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Kenneth J. Broadley
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Benson M. Kariuki
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Christopher J. Corrigan
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Jeremy P.T. Ward
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Paul J. Kemp
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Daniela Riccardi
Schools of Biosciences (P.L.Y., P.H., M.W.S., R.B., P.J.K., D.R.), Pharmacy (E.J.K., W.R.F., K.J.B.), and Chemistry (B.M.K.), Cardiff University, Cardiff, United Kingdom; Institute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria (M.W.S.); TissueGnostics GmbH, Vienna, Austria (R.E., R.N.); School of Dental Sciences, University of Newcastle, United Kingdom (V.T.); Woolcock Institute of Medical Research, The University of Sydney, Sydney, Australia (D.T., L.G.d.R.); and School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom (C.J.C., J.P.T.W.)
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Abstract

Asthma is still an incurable disease, and there is a recognized need for novel small-molecule therapies for people with asthma, especially those poorly controlled by current treatments. We previously demonstrated that calcium-sensing receptor (CaSR) negative allosteric modulators (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, which were originally developed for oral therapy for osteoporosis and previously tested in the clinic as a novel, single, and comprehensive topical antiasthma therapy. We address the hypotheses, using murine asthma surrogates, that topically delivered CaSR NAMs 1) abolish AHR; 2) are unlikely to cause unwanted systemic effects; 3) are suitable for topical application; and 4) inhibit airway inflammation to the same degree as the current standard of care, inhaled corticosteroids, and, furthermore, inhibit airway remodeling. All four CaSR NAMs inhibited poly-L-arginine–induced AHR in naïve mice and suppressed both AHR and airway 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, pharmacokinetics/pharmacodynamics, 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 airway remodeling.

SIGNIFICANCE STATEMENT Calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs) reduce airway smooth muscle hyperresponsiveness, reverse airway inflammation as efficiently as topical corticosteroids, and suppress airway remodeling in asthma surrogates. CaSR NAMs, which were initially developed for oral therapy of osteoporosis proved inefficacious for this indication despite being safe and well tolerated. Here we show that structurally unrelated CaSR NAMs are suitable for inhaled delivery and represent a one-stop, steroid-free approach to asthma control and prophylaxis.

Footnotes

    • Received August 8, 2020.
    • Accepted October 5, 2020.
  • This work was supported by King’s College Commercialization Institute [Grant 510798], Marie Curie “Multifaceted calcium-sensing receptor (CaSR)” Education and Training Network (ETN) [Grant 264663], and CaSR Biomedicine [Grant 675228].

  • https://doi.org/10.1124/jpet.120.000281.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 1
1 Jan 2021
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Research ArticleDrug Discovery and Translational Medicine

CaSR NAMs for Treatment of Asthma

Polina L. Yarova, Ping Huang, Martin W. Schepelmann, Richard Bruce, Rupert Ecker, Robert Nica, Vsevolod Telezhkin, Daniela Traini, Larissa Gomes dos Reis, Emma J. Kidd, William R. Ford, Kenneth J. Broadley, Benson M. Kariuki, Christopher J. Corrigan, Jeremy P.T. Ward, Paul J. Kemp and Daniela Riccardi
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 51-63; DOI: https://doi.org/10.1124/jpet.120.000281

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Research ArticleDrug Discovery and Translational Medicine

CaSR NAMs for Treatment of Asthma

Polina L. Yarova, Ping Huang, Martin W. Schepelmann, Richard Bruce, Rupert Ecker, Robert Nica, Vsevolod Telezhkin, Daniela Traini, Larissa Gomes dos Reis, Emma J. Kidd, William R. Ford, Kenneth J. Broadley, Benson M. Kariuki, Christopher J. Corrigan, Jeremy P.T. Ward, Paul J. Kemp and Daniela Riccardi
Journal of Pharmacology and Experimental Therapeutics January 1, 2021, 376 (1) 51-63; DOI: https://doi.org/10.1124/jpet.120.000281
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