Mesoionic purinone analogs as inhibitors of cyclic-AMP phosphodiesterase: comparison of several ring systems

Several simple alkyl and aralkyl derivatives of mesoionic thiazolopyrimidines (1) and mesoionic 1,3,4-thiadiazolopyrimidines (2) were found to possess theophylline-like activity as inhibitors of cyclic-AMP phosphodiesterase (PDE). Reduction of the C2-C3 double bond of 1 or replacement of the sulfur atom of 1 or 2 with an N-methyl group nearly abolishes activity. Optimal activity appears to be associated with a hydrophobic substituent at the N8 position. The five-membered ring of 1 can be replaced by a pyridine or isoquinoline nucleus without untoward effects. Preliminary kinetic data suggest that the type of enzyme inhibition produced by the mesoionic derivatives is similar to that observed for theophylline. Thus, several novel mesoionic ring systems display activity as inhibitors of cyclic-AMP PDE and can serve as lead compounds for further investigation.