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

Baker, Jillian G. and Gardiner, Sheila M. and Woolard, Jeanette and Fromont, Christophe and Jadhav, Gopal P. and Mistry, Shailesh N. and Thompson, Kevin S.J. and Kellam, Barrie and Hill, Stephen J. and Fischer, Peter M. (2017) Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB Journal . ISSN 1530-6860 (In Press)

[img] PDF - Repository staff only - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (2MB)

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.

Item Type: Article
Keywords: β-blocker, Selectivity, Heart disease, Asthma
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Depositing User: Eprints, Support
Date Deposited: 28 Mar 2017 12:20
Last Modified: 13 Oct 2017 01:19
URI: http://eprints.nottingham.ac.uk/id/eprint/41610

Actions (Archive Staff Only)

Edit View Edit View