SYNTHESIS AND CYCLIC-GMP PHOSPHODIESTERASE INHIBITORY ACTIVITY OF A SERIES OF 6-PHENYLPYRAZOLO [3,4-D]PYRIMIDONES

A series of 6-phenylpyrazolo[3,4-d]pyrimidones is described which are specific inhibitors of cGMP specific (type V) phosphodiesterase. Enzym atic and cellular activity as well as in vivo oral antihypertensive ac tivity are evaluated. A n-propoxy group at the 2-position of the pheny l ring is necessary for activity. A series of products substituted at the 5-position in addition to the 2-n-propoxy was prepared and evaluat ed. This position can accommodate many unrelated groups. Amino derivat ives were very potent but lacked metabolic stability. Substitution by carbon-linked small heterocycles provided both high levels of activity and stability. Cellular activity very often correlated with in vivo a ctivity. Among the compounds, thyl-6-(2-propoxy-5-methanesulfonamidoph enyl)-1,5- dihydropyrazolo[3,4-d]pyrimidin-4-one (38) and )phenyl)-1,5 -dihydropyrazolo[3,4-d]pyrimidin-4-one (59) displayed outstanding in v ivo activities at 5 mg/kg/os and good metabolic stabilities.