Synthesis and Cyclic GMP Phosphodiesterase Inhibitory Activity of a Series of 6-Phenylpyrazolo[3,4-d]pyrimidones

• Published in: Journal of medicinal chemistry 1996-04, Vol.39 (8), p.1635-1644
• Main Authors: Dumaître, Bernard, Dodic, Nerina
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases - antagonists & inhibitors; Animals; Antihypertensive agents; Biological and medical sciences; Cardiovascular system; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Pharmacology. Drug treatments; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Rats; Rats, Inbred SHR; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950812j

A series of 6-phenylpyrazolo[3,4-d]pyrimidones is described which are specific inhibitors of cGMP specific (type V) phosphodiesterase. Enzymatic and cellular activity as well as in vivo oral antihypertensive activity are evaluated. A n-propoxy group at the 2-position of the phenyl ring is necessary for activity. A series of products substituted at the 5-position in addition to the 2-n-propoxy was prepared and evaluated. This position can accommodate many unrelated groups. Amino derivatives 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 activity. Among the compounds, 1,3-dimethyl-6-(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (38) and 1-ethyl-3-methyl-6-(2-propoxy-5-(4-methylthiazol-2-yl)phenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (59) displayed outstanding in vivo activities at 5 mg/kg/os and good metabolic stabilities.