Synthesis and structure-activity relationships of pyrazolo[4,3-d]pyrimidin-7-ones as adenosine receptor antagonists.
A series of 21 1,3-dialkylpyrazolo[4,3-d]pyrimidin-7-ones substituted in the 5-position with various phenyl substituents has been synthesized and found to have affinity for the adenosine A1 receptor. The potency pattern due to substituents of the phenyl ring was found to parallel that found in a previously reported 1,3-dialkyl-8-phenylxanthine series. A quantitative structure-activity relationship was developed between these two series that correctly predicted the potencies of six additional 5-substituted pyrazolo[4,3-d]pyrimidines that were synthesized during the course of the analysis. With use of the correlation as a guide, one additional 5-phenylpyrazolo[4,3-d]pyrimidine containing a 4-[[(dimethylamino)ethyl]amino]sulfonyl substituent to improve aqueous solubility was prepared. On the basis of the high correlation between adenosine binding affinities of analogously substituted xanthines and pyrazolo-[4,3-d]pyrimidines and the close superposition of the heterocyclic rings and substituents that is apparent from molecular models of these two series, it is hypothesized they fit the receptor in an analogous fashion.
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011720:Pyrazoles; D011744:Pyrimidinones; D011983:Receptors, Purinergic; C027513:N(6)-cyclohexyladenosine; D000241:Adenosine