title: Synthesis and enzymic activity of various substituted pyrazolo[1,5-a]-1,3,5-triazines as adenosine cyclic 3',5'-phosphate phosphodiesterase inhibitors.
abstract: A series of various pyrazolo[1,5-a]-1,3,5-triazines have been prepared and studied as inhibitors of cAMP phosphodiesterase isolated from bovine brain, bovine heart, and rabbit lung. A number of compounds were found to be superior to theophylline. 2-Ethyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine (35) was found to be 97 times more potent than theophylline as an inhibitor of bovine brain PDE. 8-Bromo-2,4-dimethyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine (52) showed alpha lung = 40 compared to alpha heart = 3.0. Thus, various substituents could increase or decrease the inhibition relative to the type and source of tissue from which the PDE was isolated. The most active compound was 8-bromo-4-(diethylamino)-7-phenylpyrazolo[1,3-a]-1,3,5-triazine (25), which was 185 times more potent than theophylline as an inhibitor of PDE isolated from rabbit lung. The stepwise synthesis via ring-closure procedures of requisite pyrazole intermediates, followed by electrophilic substitution in the pyrazole ring and/or nucleophilic substitution in the 1,3,5-triazine moiety, resulted in the various pyrazolo[1,5-a]1,3,5-triazines listed in Tables I and II. Structure-activity relationships are reviewed.
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D011720:Pyrazoles; D014227:Triazines; D015105:3',5'-Cyclic-AMP Phosphodiesterases