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

In the search for more potent but still short-acting beta-blockers (BB), th e methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, 2-(1-adamantyl)ethyl, a nd methylthiomethyl esters of the acidic inactive metabolite of bufuralol w ere synthesized based on the "inactive metabolite" approach. The cleavage o f the ester bond by blood and tissue esterases rapidly deactivates these co mpounds, resulting in an ultrashort duration of action. The beta-antagonist potencies and time courses of actions of the new "soft" BBs were character ized by recording ECG and intra-arterial blood pressure (BP) in rats. In th e isoproterenol-induced tachycardia model, while bufuralol at an iv dose of 1 mg/kg (3.8 mu mol/kg) diminished heart rate (HR) for at least 2 h, the e ffects of the soft drugs lasted for only 10-30 min at equimolar dose. The i nactive metabolite did not decrease HR significantly. The first four member s of this series of compounds showed the highest beta-blocking potencies, r anging 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 mu mol/kg/min, esmolol decreas ed HR and mean arterial pressure (MAP) by 40% and 60%, respectively. The so ft drugs at doses ranging only between 2 and 4 mu mol/kg/min resulted in a 20-40% decrease in HR and a 30-50% reduction in MAP. However, the time cour ses of both the bradycardic and hypotensive effects of the soft drugs were superimposable to that of esmolol, diminishing within 60 min after the disc ontinuation of the infusions.