(IMIDAZOLYLPHENYL)PYRROL-2-ONE INHIBITORS OF CARDIAC CAMP PHOSPHODIESTERASE

Seven 3-alkyl-4-aryl-1,5-dihydro-2H-pyrrol-2-ones were prepared as pot ential inhibitors of cardiac cAMP phosphodiesterase (PDE). The design of these compounds made use of rolipram, a known inhibitor of the brai n cAMP PDE isozyme, as a lead structure and was guided by a model whic h describes the features required for potent inhibition of the cardiac isozyme. Syntheses for the new compounds are described, together with the results of theoretical and crystallographic studies aimed toward ascertaining their three-dimensional structures. The activities of the se compounds as inhibitors of the cardiac and brain cAMP PDE isozymes and their positive inotropic activity in ferret papillary muscle are a lso reported. Selected compounds were further examined in an in vivo h emodynamic model. One 1H-imidazol-1-yl)phenyl]-3-methyl-2H-pyrrol-2-on e, was identified as a potent and selective positive inotropic agent a nd inhibitor of cardiac cAMP PDE.