Cardiovascular studies on different classes of soft drugs

Based on the inactive metabolite approach, three different classes of soft drugs were designed and synthesized. Their cardiovascular effects and durat ion of actions were studied in anesthetized male Sprague-Dawley rats compar ed to the traditional drugs. During the experiments ECG (leads II, aVF) and beat-to-beat blood pressure (BP) from the left carotid artery were recorde d (except during the anticholinergic studies). The soft anticholinergic met hoxycarbonylphenylcyclopentyl-N,N-dimethyltropinium methyl sulfate was as p otent as atropine in the prevention of carbachol induced bradycardia; howev er, its action only lasted up to 15-30 min, compared to 2 h of that of atro pine. In the isoproterenol-induced tachycardia model, while bufuralol at an i.v. dose of 3.8 mu mol/kg (1 mg/kg) diminished heart rate (HR) for at lea st 2 h, the effects of the soft drugs lasted for only 30-40 min at equimola r doses. The methyl-, ethyl-, isopropyl-, and tert-butyl ester-analogs of t he carboxylic acid metabolite of bufuralol showed the highest beta-blocking potencies (i.e., 30-50% of that of bufuralol). When these compounds were i nfused for 10 min at doses ranging from 2-4 mu mol/kg/min, they caused a 20 -40% decrease in HR and a 30-40% reduction in mean arterial pressure (MAP). These effects were similar to those elicited by esmolol at a dose of 20 mu mol/kg/min in respect of the kinetics and in the extent of the reductions in heart rate and MAP. The isopropyl-, the sec-butyl-, and the neopentyl-es ters of the acidic metabolite of amiodarone, with plasma hydrolytic half-li ves of 60, 240 and 300 min, were tested in the benzene/adrenaline induced v entricular tachycardia (VT) model of the rat. All drugs were administered a t a dose of 5 mu mol/kg i.v. bolus immediately followed by an infusion at 1 5 mu mol/kg/h for 2 h. It was found, that amiodarone resulted a complete su ppression of VTs at 30 min after the start of drug administration, but its effect lasted up to the total course of the experiment (up to 180 min). On the contrary, both the sec-butyl and the isopropyl-analog resulted in compl ete suppression of VTs already during the first benzene/adrenaline challeng e after drug administration (i.e., at 5 min). However, their effects disapp eared between 15 and 30 min after discontinuation of the drug infusions in accordance with the enzymatic inactivation tester hydrolysis) of these soft drugs. All these three classes of soft cardioactive drugs are good example s for highly potent but short acting drugs whose side effects might also be reduced via the retrometabolism based drug design.