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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 235; no. 1; pp. 212 - 219
• Main Authors: MUGGLI, R, TSCHOPP, T. B, MITTELHOLZER, E, BAUMGARTNER, H. R
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.10.1985
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Animals; beta-Thromboglobulin - metabolism; Biological and medical sciences; Bleeding Time; Blood Platelets - drug effects; Blood Platelets - enzymology; Blood. Blood coagulation. Reticuloendothelial system; Calcium - metabolism; Calmodulin - metabolism; Collagen - pharmacology; cyclic AMP; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 1; Dogs; Epoprostenol - pharmacology; Fibrinolytic Agents - pharmacology; Haplorhini; Humans; man; Medical sciences; Papaverine - pharmacology; Pharmacology. Drug treatments; phosphodiesterase; Platelet Aggregation - drug effects; platelets; Quinazolines - pharmacology; Rabbits; Radioimmunoassay; Serotonin - metabolism; Thrombin - pharmacology; Mechanism of action; Platelet; Antiplatelet agent
• ISSN: 0022-3565; 1521-0103

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.