2-(Alkylthio)-1,2,4-triazolo[1,5-a]pyrimidines as adenosine cyclic 3',5'-monophosphate phosphodiesterase inhibitors with potential as new cardiovascular agents

A series of new 2-(alkylthio)-5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines have been prepared as inhibitors of cAMP phosphodiesterase from various tissues. These derivatives were prepared via ring closure of various requisite 3-amino-1,2,4-triazole intermediates. 2-(Benzylthio)-5-methyl-7-(dim...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1982-01, Vol.25 (4), p.420-426
Main Authors: Novinson, T, Springer, R H, O'Brien, D E, Scholten, M B, Miller, J P, Robins, R K
Format: Article
Language:English
Subjects:
2-(alkylthio)-1,2,4-triazolo(1,5-a)pyrimidines
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
3':5'-cyclic-nucleotide phosphodiesterase
Animals
Cardiovascular Agents - chemical synthesis
Chemical Phenomena
Chemistry
Dogs
Hemodynamics - drug effects
Myocardial Contraction - drug effects
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
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Summary:A series of new 2-(alkylthio)-5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines have been prepared as inhibitors of cAMP phosphodiesterase from various tissues. These derivatives were prepared via ring closure of various requisite 3-amino-1,2,4-triazole intermediates. 2-(Benzylthio)-5-methyl-7-(dimethylamino)-1,2,4-triazolo[1,5-a]pyrimidine (15a) is 6.3 times as potent as theophylline in inhibiting cAMP PDE isolated from rabbit heart. Treatment of dogs intravenously with 5 (mg/kg)/h of 15a gave a cardiac output increase of 69%, which was largely sustained for a 2-h period after administration of drug had ceased. There was no significant increase in heart rate upon administration of 15a. Related studies with 5,7-di-n-propyl-2-(benzylthio)-1,2,4-triazolo[1,5-a]pyrimidine (22a) in five dogs showed a 31.5% increase in cardiac output with an increase in stroke volume of 34.4% with no increase in heart rate. The specificity of action of these PDE inhibitors could be due to selective binding at a certain cAMP PDE site in the cardiovascular system. Several of these compounds are candidates for further studies with a view to clinical evaluation.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00346a017