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Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease

Baker, Jillian G.; Gardiner, Sheila M.; Woolard, Jeanette; Fromont, Christophe; Jadhav, Gopal P.; Mistry, Shailesh N.; Thompson, Kevin S.J.; Kellam, Barrie; Hill, Stephen J.; Fischer, Peter M.

Authors

Jillian G. Baker

SHEILA GARDINER Sheila.Gardiner@nottingham.ac.uk
Professor of Cardiovascular Physiology

Jeanette Woolard

Christophe Fromont

Shailesh N. Mistry shailesh.mistry@nottingham.ac.uk

Kevin S.J. Thompson

Barrie Kellam

Stephen J. Hill

Peter M. Fischer



Abstract

β-Blockers reduce mortality and improve symptoms in people with heart disease. However, current clinically available β-blockers have poor selectivity for the cardiac β1-adrenoceptor (AR) over the lung β2-AR. Unwanted β2-blockade risks causing life-threatening bronchospasm and a reduction in the efficacy of β2-agonist emergency rescue therapy. Thus current life-prolonging β-blockers are contraindicated in people with both heart disease and asthma. Here we describe NDD-713 and NDD-825, novel highly β1-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays using human receptors expressed in CHO cells demonstrate that NDD-713 and NDD-825 have nanomolar β1-AR affinity, greater than 500-fold β1-AR vs β2-AR selectivity and no agonism. Studies in conscious rats demonstrated that they are orally bioavailable and cause pronounced β1-mediated reduction of heart rate while showing no effect on β2-mediated hindquarters vasodilatation. The compounds also have good disposition properties and show no adverse toxicological effects. They potentially offer a truly cardioselective β-blocker therapy for the large number of people with heart and respiratory, or peripheral vascular comorbidities.

Journal Article Type Article
Publication Date Jul 31, 2017
Journal FASEB Journal
Print ISSN 0892-6638
Electronic ISSN 1530-6860
Publisher Federation of American Society of Experimental Biology
Peer Reviewed Peer Reviewed
Volume 31
Issue 7
Pages 3150-3166
APA6 Citation Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., …Fischer, P. M. (2017). Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB Journal, 31(7), 3150-3166. https://doi.org/10.1096/fj.201601305R
DOI https://doi.org/10.1096/fj.201601305R
Keywords β-blocker, Selectivity, Heart disease, Asthma
Publisher URL http://www.fasebj.org/content/31/7/3150
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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