Novel selective ?1-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.

Abstract

?-Blockers reduce mortality and improve symptoms in people with heart disease. However, current clinically available ?-blockers have poor selectivity for the cardiac ?1-adrenoceptor (AR) over the lung ?2-AR. Unwanted ?2-blockade risks causing life-threatening bronchospasm and a reduction in the efficacy of ?2-agonist emergency rescue therapy. Thus current life-prolonging ?-blockers are contraindicated in people with both heart disease and asthma. Here we describe NDD-713 and NDD-825, novel highly ?1-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 ?1-AR affinity, greater than 500-fold ?1-AR vs ?2-AR selectivity and no agonism. Studies in conscious rats demonstrated that they are orally bioavailable and cause pronounced ?1-mediated reduction of heart rate while showing no effect on ?2-mediated hindquarters vasodilatation. The compounds also have good disposition properties and show no adverse toxicological effects. They potentially offer a truly cardioselective ?-blocker therapy for the large number of people with heart and respiratory, or peripheral vascular comorbidities.

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

• Journal Article Type: Article
• Acceptance Date: Mar 20, 2017
• Online Publication Date: Apr 11, 2017
• Publication Date: Jul 31, 2017
• Deposit Date: Mar 28, 2017
• Publicly Available Date: Apr 11, 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
• DOI: https://doi.org/10.1096/fj.201601305R
• Keywords: ?-blocker, Selectivity, Heart disease, Asthma
• Public URL: https://nottingham-repository.worktribe.com/output/874855
• Publisher URL: http://www.fasebj.org/content/31/7/3150