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

β-Blockers reducemortality andimprove symptoms inpeople withheartdisease;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 reduced efficacy of β₂-agonist emergency rescue therapy. Thus, current life-prolonging β-blockers are contraindicated in patients with both heart disease and asthma. Here, we describeNDD-713 and -825, novel highly β₁-selective neutral antagonists with good pharmaceutical properties that can potentially overcome this limitation. Radioligand binding studies and functional assays that use human receptors expressed inChinesehamster ovary cellsdemonstrate that NDD-713 and-825 have nanomolar β₁-AR affinity >500-fold β₁-AR vs. β₂-AR selectivity and no agonism. Studies in conscious rats demonstrate that these antagonists are orally bioavailable and cause pronounced β₁-mediated reduction of heart rate while showing no effect on β₂-mediated hindquarters vasodilatation. These compounds also have good disposition properties and show no adverse toxicologic effects. They potentially offer a truly cardioselective β-blocker therapy for the large number of patientswith heart and respiratory or peripheral vascular comorbidities.