TOWARD THE IDENTIFICATION OF THE CARDIAC CGMP INHIBITED-PHOSPHODIESTERASE CATALYTIC SITE

Cyclic nucleotide phosphodiesterases (PDEs) comprise a complex group o f enzymes; five major PDE families or classes with distinctive propert ies have been identified. Among these a great deal of interest has rec ently been focused on the so called cGMP-inhibited low K-m cAMP phosph odiesterase (cGI PDE) or PDE III. A number of positive inotropic agent s, including the well-known milrinone, display a specific inhibition o f PDE III as primary mechanism of action. Recent studies have been car ried 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 enzyma tic inhibition. The DISCO (DIStance COmparison) strategy has been appl ied on a set of compounds taken from literature and a milrinone analog ue previously synthesized by us, all of which are characterized by a m arked inotropic effect but with varying degrees of enzyme selectivity. A common pharmacophoric model was derived, validated and considered a s starting point to perform a 3D-SAR study using the GRID force field and PCA (Principal Component Analysis) with the aim of rationally desi gning more selective inhibitors. This paper presents the results of th is theoretical approach.