Novel selective β ₁ ‐adrenoceptor antagonists for concomitant cardiovascular and respiratory disease

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 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 describe NDD-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 in Chinese hamster ovary cells demonstrate 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 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 β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.

β-Blockers, heart disease and COPD: current controversies and uncertainties

“…Such molecules have recently been synthesised (with β1-selectivity vs β2-selectivity of 500-fold to 5000-fold87) and have been proven to be orally bioavailable and highly β1-selective in animals. Such a drug would circumnavigate the entire bronchospasm issue, yet still provide the well-proven cardiovascular β-blocker benefit.…”

A photoswitchable ligand targeting β1-adrenoceptor enables light-control of the cardiac rhythm

“…The fact that good selectivity is achieved when the compounds were disposed in their longer isomeric form was in good agreement with the recently reported molecular mechanisms governing β 1 /β 2 subtype selectivity. [32,37,38] Both β 1 -AR and β 2 -AR present the same residues at the orthosteric site, only some residues at the edge of the pocket are different. Thus, long ligands may directly interact with these residues resulting in differential modulation of the two receptor subtypes.…”

Linked biaromatic compounds as cardioprotective agents

“…Therefore, in later works on the search for β‐blockers, considerable attention is paid to their β1‐selectivity. [ 255 ]…”

“…These ligands are suggested by authors as promising candidates for the development of β‐blockers devoid of β 2 ‐AR‐mediated adverse effects of bronchospasm and vasoconstriction and may prove beneficial in patients with concomitant cardiovascular and respiratory disease or limb ischemia (peripheral vascular disease). [ 255 ]…”

“…These ligands are suggested by authors as promising candidates for the development of β-blockers devoid of β 2 -AR-mediated adverse effects of bronchospasm and vasoconstriction and may prove beneficial in patients with concomitant cardiovascular and respiratory disease or limb ischemia (peripheral vascular disease). [255] The latest example of the creation of compounds with β-blocking properties in the LBC series is the work of Ghabbour et al from Mansoura University (Egypt, 2014). Based on the structures of the β-blockers IPS 339 and falintolol, which contain oxime groups, the authors have constructed a number of compounds 84, among which 3,4dimethoxyphenethyl derivatives with an oxime-containing linker length of 10 bonds had the highest potential according to molecular docking data (Figure 55).…”