Pharmacology of a potent, new antithrombotic agent, 6-methyl-1,2,3,5- tetrahydroimidazo[2, 1-b] quinazolin-2-one hydrochloride monohydrate

JS Fleming, JP Buyniski, RL Cavanagh and ME Bierwagen

The effect of 6-methyl-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2- one hydrochloride monohydrate (BL-3459) on platelet function and experimental thrombosis was evaluated in a series of in vitro, ex vivo and in vivo animal experiments. Potent inhibition of platelet aggregation for BL-3459 was demonstrated by both in vitro and ex vivo techniques. In vitro, EC50 levels were less than 1 mug/ml regardless of the aggregating substance used or the species of animal from which platelet-rich plasma was obtained. After oral administration to rats and dogs, BL-3459 was rapidly absorbed and had a long duration of action. Ex vivo ED50 values were in the range of 2 to 3 mg/kg p.o. In addition, BL-3459 (1-10 mg/kg) demonstrated significant oral activity in a variety of in vivo animal models. BL-3459 inhibited elevation in screen filtration pressure induced by hemorrhage in dogs, endotoxemic death in rats, intravascular thrombosis produced by electrical stimulation of the carotid artery of the dog and thrombosis induced by means of a biolaser in the microvasculature of the rabbit ear chamber. In contrast to acetylsalicylic acid, BL-3459 had little effect on bleeding time in guinea pigs. Oral or intraduodenal administration of BL-3459 to dogs lowered aortic blood pressure, stroke volume and peripheral vascular resistance, while elevating cardiac rate and cardiac contractile force. Thus, it had little effect on the estimated cardiac output. These cardiovascular effects were mediated, in large part, through direct-acting mechanisms. BL-3459 exhibited weak antiserotonin activity in isolated smooth muscle preparations. While the precise mechanism of action of BL-3459 has not yet been determined, indications are that the compound may prove useful in the prevention of intravascular thrombosis.

Volume 194, Issue 2, pp. 435-449, 08/01/1975
Copyright © 1975 by American Society for Pharmacology and Experimental Therapeutics