title: 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.
abstract: This study with the new analog Ro 15-2041 (7-bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)-on e) 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 microM). 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 microM. 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.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004285:Dogs; D011464:Epoprostenol / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D010208:Papaverine / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D011817:Rabbits; D011863:Radioimmunoassay; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D001620:beta-Thromboglobulin / Q000378:metabolism
chemical_list: D002147:Calmodulin; D005343:Fibrinolytic Agents; D011799:Quinazolines; D001620:beta-Thromboglobulin; D012701:Serotonin; C046655:Ro 15-2041; D003094:Collagen; D010208:Papaverine; D011464:Epoprostenol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D013917:Thrombin; D002118:Calcium