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.

By means of left ventricular pressure-volume relationships, the authors investigated left ventricular contractility, the arterial loading conditions, and how their interaction affects myocardial energetics in human patients with idiopathic dilated cardiomyopathy.The coupling condition in these patients was far from the optimal.Moreover, the cardiovascular performance of these patients was severely depressed, both mech. and energetically even in the mild to moderate cases.Dobutamine, MS-857 and OPC-18790 similarly improved the relationship between contractility and vascular load and increased the work efficiency, but no enough to optimize the coupling condition.These inotropic agents had minimal but different effects on mech. efficiency.OPC-18790 increased contractility, decreased myocardial oxygen consumption and consequently improved mech. efficiency.OPC-18790 may be beneficial in the treatment of failing hearts by improving hemodynamics without increasing myocardial oxygen demand.