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. 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-dihydr opyrazolo[3,4-d]pyrimidin-4-one (38) and 1-ethyl-3-methyl-6-(2-propoxy-5-(4-methylthiazol-2-yl)phenyl -1,5-dihy dropyrazolo[3,4-d]pyrimidin-4-one (59) displayed outstanding in vivo activities at 5 mg/kg/os and good metabolic stabilities.
Dumaître
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B
Laboratories Glaxo Wellcome Centre de Recherches, Les Ulis Cedex, France.
Dodic
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D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D015106:3',5'-Cyclic-GMP Phosphodiesterases