Synthesis and phosphodiesterase activity of carboxylic acid mimetics of cyclic guanosine 3',5'-monophosphate.
Synthetic analogs of the natural product griseolic acid in which a guanine base is substituted for the adenine have been prepared. The best of these compounds inhibits a cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase preparation with an IC50 of 0.34 microM but is a very weak inhibitor of a cyclic adenosine 3',5'-monophosphate (cAMP) phosphodiesterase. An exploration of stereochemistry indicates that the configuration of the carboxylic acids and the ring fusion in the inhibitors is important for potent cGMP PDE inhibition. PDE inhibition is not sensitive to the presence of the 2' or 4' oxygen atoms in the ribose, but inhibition is decreased when the 3' oxygen is removed. A selected group of analogs in which a monocarboxylic acid is present are poor inhibitors. The structure-activity relationship is consistent with the carboxylic acid functionality acting as a mimetic for the phosphate anion in cGMP. This concept is supported by a conformational analysis of two of the inhibitors.
Schering-Plough Research Institute, Kenilworth, New Jersey 07033.
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D003198:Computer Simulation; D006152:Cyclic GMP / Q000031:analogs & derivatives*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; C046499:griseolic acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP; D000241:Adenosine