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-(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.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002317:Cardiovascular Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology
D002317:Cardiovascular Agents; D011743:Pyrimidines; D015105:3',5'-Cyclic-AMP Phosphodiesterases