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

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

Safety of Concomitant Potassium-sparing Diuretics in Angiotensin-converting Enzyme-inhibitor Therapy in Severe Congestive-heart-failure

The safety of concomitant use of angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diurectics (PSD) in severe heart failure remains a controversial issue. The database of the recently reported double-blind international trial, ''Xamoterol in Severe Heart Failure,'' was investigated to elucidate this question. Of 516 patients with New York Heart Association (NYHA) class III-IV, despite diuretics and ACE inhibitor therapy, 352 were randomized to xamoterol, a beta(1) partial agonist, and 164 were randomized to placebo. During the 13-week study, 28% of all patients (xamoterol, 104; placebo, 42) received potassium-sparing diuretics. All groups were comparable in hemodynamics and dose of other diuretics. At study end, patients with or without PSD showed no significant differences in serum K+ or creatinine, independent of xamoterol or placebo therapy