Soft drugs. 12. Design, synthesis, and evaluation of soft bufuralol analogues.

In the search for more potent but still short-acting beta-blockers (BB), the methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, 2-(1-adamantyl)ethyl, and methylthiomethyl esters of the acidic inactive metabolite of bufuralol were synthesized based on the "inactive metabolite" approach. The cleavage of the ester bond by blood and tissue esterases rapidly deactivates these compounds, resulting in an ultrashort duration of action. The beta-antagonist potencies and time courses of actions of the new "soft" BBs were characterized by recording ECG and intra-arterial blood pressure (BP) in rats. In the isoproterenol-induced tachycardia model, while bufuralol at an iv dose of 1 mg/kg (3.8 micromol/kg) diminished heart rate (HR) for at least 2 h, the effects of the soft drugs lasted for only 10-30 min at equimolar dose. The inactive metabolite did not decrease HR significantly. The first four members of this series of compounds showed the highest beta-blocking potencies, ranging between 25% and 50% of that of bufuralol. Next, the effects of these most active compounds on resting HR and BP were evaluated in comparison to esmolol. Infused for 10 min at a rate of 20 micromol/kg/min, esmolol decreased HR and mean arterial pressure (MAP) by 40% and 60%, respectively. The soft drugs at doses ranging only between 2 and 4 micromol/kg/min resulted in a 20-40% decrease in HR and a 30-50% reduction in MAP. However, the time courses of both the bradycardic and hypotensive effects of the soft drugs were superimposable to that of esmolol, diminishing within 60 min after the discontinuation of the infusions.