Mesoionic xanthine analogues: 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. 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.