MS-857

Cyclic nucleotide phosphodiesteras (PDEs) comprise a complex group of enzymes; five major PDE families or classes with distinctive properties have been identified. Among these a great deal of interest has recently been focused on the so called cGMP-inhibited low K(m) cAMP phosphodiesterase (cGI PDE) or PDE III. A number of positive inotropic agents, including the well-known milrinone, display a specific inhibition of PDE III as primary mechanism of action. Recent studies have been carried out to develop a pharmacophore model of the PDE III active site. We therefore performed molecular modelling and 3D-SAR studies so as to better define structural requirements for potent and selective enzymatic inhibition. The DISCO (DIStance COmparison) strategy has been applied on a set of compounds taken from literature and a milrinone analogue previously synthesized by us, all of which are characterized by a marked inotropic effect but with varying degrees of enzyme selectivity. A common pharmacophoric model was derived, validated and considered as starting point to perform a 3D-SAR study using the GRID force field and PCA (Principal Component Analysis) with the aim of rationally designing more selective inhibitors. This paper presents the results of this theoretical approach.

This study was designed to compare the influence of beta-adrenergic stimulation (dobutamine) and a selective phosphodiesterase inhibitor (MS-857) on left ventricular diastolic performance and Doppler transmitral flow velocity patterns in patients with congestive heart failure and to elucidate the mechanisms for changes in early diastolic filling induced by each agent.

Both beta-adrenergic agonists and phosphodiesterase inhibitors act through the cyclic adenosine monophosphate pathway. However, it is controversial whether they have similar effects on diastolic performance. No previous studies have investigated the effects of these agents on Doppler-derived measurements of diastolic filling. We hypothesized that they would have different effects on early diastolic filling in patients with congestive heart failure.

Twenty patients with chronic congestive heart failure resulting from idiopathic dilated cardiomyopathy were randomized to receive intravenous infusion of dobutamine (5 micrograms/kg body weight per min, n = 10) or oral administration of MS-857 (15 mg, n = 10). Transmitral flow velocity patterns were obtained with simultaneous recordings of pressure-volume loops using a conductance catheter with a micromanometer tip before and after drug administration.

Left ventricular filling pressure was reduced by both agents. Dobutamine decreased the time constant of isovolumetric relaxation and increased the difference between pulmonary artery wedge pressure at the peak of the v wave and left ventricular minimal pressure (10 +/- 3 to 12 +/- 4 mm Hg, p < 0.01) and peak early filling velocity (47 +/- 7 to 56 +/- 11 cm/s, p < 0.01). The diastolic pressure-volume relation showed a leftward shift in all patients. In contrast, MS-857 did not affect the time constant but maintained the pressure difference (9 +/- 3 to 8 +/- 3 mm Hg, p = NS) and peak early filling velocity (50 +/- 7 to 49 +/- 12 cm/s, p = NS). The diastolic pressure-volume relation after MS-857 showed a downward shift in most patients.

These results indicate that beta-adrenergic stimulation and phosphodiesterase inhibitors have different effects on early diastolic filling through different mechanisms in patients with congestive heart failure.