Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide.
Evaluation of a series of lactam heterocyclic analogues of cilostamide (2) as inhibitors of cyclic AMP phosphodiesterase derived from both human platelets and rat heart in comparison with their corresponding methoxy-substituted heterocycles has revealed that the N-cyclohexyl-N-methyl-4-oxybutyramide side chain of 2 is an important lipophilic and/or steric pharmacophore. Attachment of this side chain to the parent heterocycle of the potent cyclic AMP phosphodiesterase inhibitor anagrelide (3) afforded the hybrid structure RS-82856 (1), shown to be more potent than either of its progenitors as an inhibitor of cyclic AMP phosphodiesterase or of ADP-induced platelet aggregation. The available in vitro data suggest that 1 possesses potentially useful antithrombotic and cardiotonic properties.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009206:Myocardium / Q000201:enzymology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones; D051381:Rats; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011799:Quinazolines; D011804:Quinolines; D015363:Quinolones; C021294:cilostamide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C021139:anagrelide