Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory diseaseTools 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. and Fischer, Peter M. (2017) Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB Journal, 31 (7). pp. 3150-3166. ISSN 1530-6860 Full text not available from this repository.
Official URL: http://www.fasebj.org/content/31/7/3150
Abstractβ-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.
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