INOTROPIC AGENTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NEW MILRINONE RELATED CAMP PDE-III INHIBITORS

The synthesis of 6-substituted 5-acyl-1,2-dihydro-2-oxo-3-pyridinecarb onitriles 1b,c, 6,7,8-hexahydro-2,5-dioxo-3-quinolinecarbonitriles 1d- g and esters of no-1,6-dihydro-2-methyl-6-oxo-3-pyridinecarboxylic aci d 2b-e is described. In the case of le and If, a careful elucidation o f the reaction mechanism is discussed. As milrinone analogues, the abo ve compounds were tested on contractile activity and frequency rate of spontaneously beating atria from reserpine-treated guinea pigs. The m ethyl and the benzyl esters 2b and 2e showed an appreciable positive i notropic activity when compared to milrinone. A fitting study with the DISCO (Distance Comparison) model has been carried out on 2e. This mo deling approach allowed for the improvement of the pharmacophoric requ irements for a better interaction with the cAMP-specific PDE (PDE III) , thought to be the final biological target of these cardiotonic agent s.