Benz-fused mesoionic xanthine analogs as inhibitors of cyclic-AMP phosphodiesterase

Journal of Medicinal Chemistry
1981.0

Abstract

Gaseous [13N]ammonia produced by the 16O(p,α)13N reaction was swept into buffered solutions to synthesize 13N-labeled L-glutamate, L-alanine, L-glutamine, and L-aspartate using enzyme columns. The myocardial residue fraction of these amino acids was studied in open-chest dogs via a single pass uptake technique, showing a triexponential time-activity curve with a slow clearance phase. Tomographic imaging with ECAT in ischemic dogs revealed that ratios of 13N-labeled amino acid activity to [13N]ammonia flow indices were consistently >1, indicating retained activity in ischemic myocardium. Additionally, a series of 16 benz-fused mesoionic thiazolo[3,2-a]pyrimidine analogues were prepared as cyclic-AMP phosphodiesterase (PDE) inhibitors. These benz-fused analogues were more active than nonfused counterparts against bovine heart PDE. Structural modifications (e.g., R1 cyclopropyl substitution, 8-ethoxy group introduction) enhanced activity, and mesoionic character was critical for potency, as nonmesoionic compounds were less active. Solubility issues precluded reliable IC50 determination for some analogues.

Knowledge Graph

Similar Paper

Benz-fused mesoionic xanthine analogs as inhibitors of cyclic-AMP phosphodiesterase
Journal of Medicinal Chemistry 1981.0
Mesoionic xanthine analogs: phosphodiesterase inhibitory and hypotensive activity
Journal of Medicinal Chemistry 1981.0
Mesoionic purinone analogs as inhibitors of cyclic-AMP phosphodiesterase: comparison of several ring systems
Journal of Medicinal Chemistry 1981.0
Cyclic GMP phosphodiesterase inhibitors. 1. The discovery of a novel potent inhibitor, 4-[[3,4-(methylenedioxy)benzyl]amino]-6,7,8-trimethoxyquinazoline
Journal of Medicinal Chemistry 1993.0
Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogs of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline
Journal of Medicinal Chemistry 1988.0
2-(Alkylthio)-1,2,4-triazolo[1,5-a]pyrimidines as adenosine 3',5'-monophosphate phosphodiesterase inhibitors with potential as new cardiovascular agents
Journal of Medicinal Chemistry 1982.0
Cyclic GMP Phosphodiesterase Inhibitors. 2. Requirement of 6-Substitution of Quinazoline Derivatives for Potent and Selective Inhibitory Activity
Journal of Medicinal Chemistry 1994.0
Synthesis and enzymic activity of 6-carbethoxy- and 6-ethoxy-3,7-disubstituted pyrazolo[1,5-a]pyrimidines and related derivatives as adenosine cyclic 3',5'-phosphate phosphodiesterase inhibitors
Journal of Medicinal Chemistry 1982.0
Synthesis and enzymic activity of some new purine ring system analogs of adenosine 3'5'-cyclic monophosphate
Journal of Medicinal Chemistry 1992.0
1-(4-Aminobenzyl)- and 1-(4-aminophenyl)isoquinoline derivatives: synthesis and evaluation as potential irreversible cyclic nucleotide phosphodiesterase inhibitors
Journal of Medicinal Chemistry 1983.0