7-BROMO-1,5-DIHYDRO-3,6-DIMETHYLIMIDAZO[2,1-B]QUINAZOLIN-2(3H)-ONE (RO 15-2041), A POTENT ANTITHROMBOTIC AGENT THAT SELECTIVELY INHIBITS PLATELET CYCLIC AMP-PHOSPHODIESTERASE

  • 1 January 1985
    • journal article
    • research article
    • Vol. 235  (1) , 212-219
Abstract
This study with the new analog Ro 15-2041 (7-bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)-one) confirms and substantially extends the activity spectrum of imidazoquinazolinones as potent platelet function inhibitors. Ro 15-2041 inhibited platelet aggregation induced by all common platelet agonists in platelet-rich plasma obtained from various species including man (IC50 = 1-3 .mu.M). The compound potentiated platelet inhibition by prostacyclin, the prostacyclin-induced increase of intraplatelet cyclic (c) AMP levels and inhibited the collagen-induced release of serotonin and .beta.-thromboglobulin. Ro 15-2041 reduced the increase and accelerated the normalization of cytosolic free Ca++ in thrombin-stimulated human platelets. Ro 15-2041 is a potent (IC50 = 70 nM) and selective inhibitor of platelet cAMP-phosphodiesterase activity. Whereas Ro 15-2041 caused complete inhibition of cAMP-phosphodiesterase activity in human platelet supernatants, breakdown of cAMP in cardiac homogenates was depressed to maximally 50%. In human brain and rabbit uterus Ro 15-2041 was at least 1000 times less potent. By comparison, papaverine fully inhibited phosphodiesterase activity in all four tissues with similar IC50 values of about 5 .mu.M. Furthermore, Ro 15-2041 selectively inhibited cAMP-phosphodiesterase activity of a bovine calmodulin-independent but not of a calmodulin-dependent enzyme preparation. The compound exhibited significant p.o. activity in various ex vivo and in vivo platelet function tests. In Stumptail monkeys the ID50 was about 2.5 .mu.mol/kg 2 and 4 hr after dosing. After 5 .mu.mol/kg p.o. the platelet inhibitory effect persisted for more than 6 hr and was paralled by an increase in cardiac rate. In rabbits, the compound prolonged the bleeding time and inhibited the platelet drop and the in vivo release of platelet specific proteins after i.v. injection of collagen fibrils. The results indicate that Ro 15-2041 inhibits platelet function by increasing cAMP levels through inhibition of cAMP-phosphodiesterase activity, thereby increasing the capacity of platelets to prevent and to reverse Ca++ transients.

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