2-PYRIDONE DERIVATIVES AS INOTROPIC AGENTS - SYNTHESIS, PHARMACOLOGY AND MOLECULAR MODELING STUDY

In pursuit of novel milrinone analogues like cardiotonic drugs which a ct through selective inhibition of cardiac cAMP PDE III, various serie s of 2-oxo-3-pyridinecarbonitriles, 2,5-dioxo-3-quinolinecar-bonitrile s, 5-cyano-6-oxo-3-pyridinecarboxylates and related 3- and 5- acetyl d erivatives were prepared and evaluated as inotropic and chronotropic a gents in spontaneously beating atria from reserpine-treated guinea pig s. The more active compounds, namely 9a, 12f, 15a, 15b and 22f were st udied to evaluate their mechanism of action. 15a, the more representat ive inotropic agent of the above derivatives, competitively inhibited PDE III with an affinity such as that of milrinone. Molecular modeling studies using the DISCO (DIStance COmparison) module were carried out on selected conformationally restrained structures and on 15a to defi ne a possible pharmacophoric model.