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

beta-Blockers reduce mortality and improve symptoms in people with heart disease; however, current clinically available beta-blockers have poor selectivity for the cardiac I31-adrenoceptor (AR) over the lung I32-AR. Unwanted beta 2 blockade risks causing life-threatening bronchospasm and reduced efficacy of beta 2-agonist emergency rescue therapy. Thus, current life-prolonging beta-blockers are contraindicated in patients with both heart disease and asthma. Here, we describe NDD-713 and-825, novel highly beta(1)-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed in Chinese hamster ovary cells demonstrate that NDD-713 and-825 have nanomolar beta(1)-AR affinity >500-fold beta(1)-AR vs. beta(2)-AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced beta(1)-mediated reduction of heart rate while showing no effect on I32-mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective beta-blocker therapy for the large number of patients with heart and respiratory or peripheral vascular comorbidities. Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., Thompson, K. S. J., Kellam, B., Hill, S. J., Fischer, P. M. Novel selective I31-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.