NOVEL AND POTENT ADENOSINE 3',5'-CYCLIC PHOSPHATE PHOSPHODIESTERASE-III INHIBITORS - THIAZOLO[4,5-B][1,6]NAPHTHYRIDIN-2-ONES

The transformation of 3-bromo-1,6-naphthyridin-2(1H)-ones 8 to thiazol o[4,5-b][1,6]naphthyridin-2(1H)-ones 12 resulted in a 2-9-fold increas e in cAMP phosphodiesterase (PDE) III inhibitory potency. Unlike the s econdary binding sites on the cAMP PDE III isozyme which interact with the methyl group of milrinone (2) and CI-930 (4), the site which inte racts with the 5-substituents of 1,6-naphthyridin-2(1H)-ones and the 8 -substituents of thiazolo[4,5-b][1,6]-naphthyridin-2(1H)-ones 12 is ab le to accommodate a diverse group of substituents which have different steric and electronic requirements.