A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C

Abstract

A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] 2 In anaesthetized guinea-pigs, dogs and primates, a bolus i.v. injection of BWA746C, (0.001-1.0 mg kg-') caused a significant, dose-related increase in ventricular dP/dt, and reduction in diastolic blood pressure, with small increases in heart rate. In these species, a significantly higher dose of BW A746C was required to lower blood pressure by 30% from basal, than was needed to raise ventricular dP/dt by 50% over basal.3 In anaesthetized guinea-pigs and dogs, bolus i.v. injections of sulmazole (0.1-10.0mg kg-')caused similar effects to those observed with BW A746C. In these species, however, there was no significant difference between the dose of sulmazole required to lower blood pressure by 30% from basal and that required to raise ventricular dP/dt by 50%. 4 In conscious dogs, i.v. infusion of BW A746C (to a total dose of 0.3 mg kg-') caused a significant increase in ventricular dP/dt, but no significant change in either diastolic blood pressure or heart rate. 5 In cell-free biochemical assays, there were no clear differences between the observed activities of BW A746C and sulmazole. Both compounds are cyclic nucleotide phosphodiesterase inhibitors with similar potencies and selectivities for the Type III enzyme (IC-, BW A746C = 3.0 ± 0.5 x 10-'M, sulmazole 5.0 ± 1.9 x 10-' M). The compounds had little or no effects on sarcolemmal Na+/ K+-ATPase, Ca"+ ATPase or Na+/Ca2" exchange, and sulmazole, but not BW A746C, had a small, stimulatory effect on myofibrillar ATPase.6 In anaesthetized guinea-pigs and dogs, BW A746C was significantly more potent as a positive inotrope than sulmazole. In contrast with sulmazole, BW A746C produced its inotropic effects at significantly lower doses than those required to reduce diastolic blood pressure. This was also apparent from the results obtained in the anaesthetised primates and the conscious dogs. It was therefore concluded that the inotropic/vasodilator profile of BW A746C favours its positive inotrope activity.This profile cannot be explained on the basis of any biochemical differences from sulmazole.

Inotropic Activities of Imidazopyridines

“…ED50 values for 19 (0.28 mg kg-') and 5 (0.91 mg kg-'); (c) the most potent analogues possessed electron-withdrawing substituents in the 4'-position, i.e. ED50 values for 16 and 18 (0.014 mg kg-' in both cases); (d) compound 21, although one of the most potent inotropes in vifro (pA50% 6.00), displayed relatively weak in vivo effects (ED50 value 2.3 mg kg-I).…”