Pharmacology of a potent, new antithrombotic agent, 1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one (BMY-20844).
The effects of 1,3-dihydro-7,8-dimethyl-2H-imidazo[4,5-b]quinolin-2-one (BMY-20844) on platelet function and experimental thrombosis were evaluated in a series of in vitro, ex vivo and in vivo experiments. The compound inhibited platelet aggregation in vitro in platelet rich plasma obtained from humans, rats and rabbits with EC50s of less than 1 microgram/ml when aggregation was induced by ADP, collagen or thrombin. Supra-additive interaction against ADP aggregation was also observed when BMY-20844 was combined with prostacyclin. BMY-20844 was orally active with an ex vivo ED50 in the rat of 3.2 mg/kg vs ADP. Significant antithrombotic activity was observed in two animal models (laser induced thrombosis in the microcirculation of the rabbit ear and coronary artery thrombosis in the dog). Inhibitions of 52% at 3 mg/kg p.o. in the laser model and 100% at 1 mg/kg i.d. in the coronary artery thrombosis model were obtained. Modest inotropic and hemodynamic effects were observed in ferrets and dogs. BMY-20844 was found to be a potent, specific inhibitor of platelet low Km cyclic AMP phosphodiesterase.
Buchanan
J O
JO
Department of Cardiovascular Biochemistry, Bristol-Myers Company, Wallingford, Connecticut.
Fleming
J S
JS
Cornish
B T
BT
Baryla
U M
UM
Gillespie
E
E
Stanton
H C
HC
Seiler
S M
SM
Keely
S L
SL
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004357:Drug Synergism; D011464:Epoprostenol / Q000494:pharmacology; D005289:Ferrets; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008252:Macaca fascicularis; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D013927:Thrombosis / Q000188:drug therapy
D005343:Fibrinolytic Agents; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; C062501:1,3-dihydro-7,8-dimethyl-2H-imidazo(4,5-b)quinolin-2-one; D011464:Epoprostenol; D015105:3',5'-Cyclic-AMP Phosphodiesterases