Mesoionic xanthine analogs: phosphodiesterase inhibitory and hypotensive activity

Several mesoionic thiazolo[3,2-alphapyrimidines and mesoionic 1,3,4-thiadiazol[3,2-alpha-pyrimidines were evaluated as inhibitors of cyclic-AMP phosphodiesterase. While small alkyl substituents at the 6 position have no significant effect on activity, phenyl and benzyl substituents enhance activity....

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Bibliographic Details
Published in:Journal of medicinal chemistry 1981-06, Vol.24 (6), p.658-661
Main Authors: Glennon, Richard A, Rogers, Michael E, Smith, J. Doyle, El-Said, M. K, Egle, John L
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
3':5'-cyclic-nucleotide phosphodiesterase
Animals
Antihypertensive Agents
Blood Pressure - drug effects
Cattle
In Vitro Techniques
inhibition
Male
Pyrimidinones - chemical synthesis
Rats
Structure-Activity Relationship
Thiadiazines - chemical synthesis
Thiazines - chemical synthesis
Xanthine
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Summary:Several mesoionic thiazolo[3,2-alphapyrimidines and mesoionic 1,3,4-thiadiazol[3,2-alpha-pyrimidines were evaluated as inhibitors of cyclic-AMP phosphodiesterase. While small alkyl substituents at the 6 position have no significant effect on activity, phenyl and benzyl substituents enhance activity. Mesoionic structures such as 1 (R2 = H; R8 = Et) possess 20 to 40 times the activity of theophylline when the R6 substituent is phenyl or 4-chlorobenzyl. methyl and ethyl substitution at the 2 position essentially abolishes activity. Although plagued by solubility problems, several of the mesoionic derivatives were found to display weak hypotensive effects in vivo.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00138a002