2- substituted 5-acetyl-1,6-dihydro-6-oxo-3-pyridinecarboxylates: synthesis and cardiotonic activity

A series of milrinone analogues, namely 2-substituted 5-acetyl-1,6-dihydro-6-oxo-3-pyridinecarboxylates 17-23, related carboxylic acids 24-27 and 6-substituted 3-acetyl 1,2-dihydro-2-pyridones 28 and 29, in which the cyano group was replaced by the acetyl function, was prepared. All the compounds were tested for their effects on contractile force and frequency rate of spontaneously beating atria. The cardiac effect of esters 17, 20, acid 26 and ketone 29, which are the most significant inotropic agents, was also investigated in electrically driven atria in the absence and in the presence of beta blocker propranolol or of adenosine deaminase. Their inhibitory effect on Type III PDE was also determined. The experimental data show that the nature of the substituent on position 3 and 2 of the pyridone ring seems to be responsible for the involvement of different mechanisms that induce the inotropic response.