HL 725, an extremely potent inhibitor of platelet phosphodiesterase and induced platelet aggregation in vitro

The new pyrimido-isoquinoline compound HL 725 is an extremely potent inhibitor of the aggregation of human platelets induced in vitro by ADP, collagen, Thrombin and epinephrine. The aggregation induced by 0,5 mM arachidonic acid is inhibited about 50% with 50 pM HL 725. Thus the potency of HL 725 is higher than that of prostacyclin, the most active natural inhibitor of aggregation. We hypothesize that HL 725 inhibits the enzymatic degradation of cyclic adenosine 3', 5'-monophosphate (cAMP) in the platelets. In accordance with this proposal is the strong inhibitory action on cAMP phosphodiesterase extracted from human platelets. About 250 pM HL 725 inhibited 50% of the activity of this Enzyme at a substrate concentration of 0.5 microM. A marked elevation of cAMP levels in human platelets could be demonstrated after incubation in vitro with 100 nM HL 725.