Summary
SR 46349 (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorophenyl)propen-1-yl]
phenol, hemifumarate) is the first member of a newly-developed 5-HT2 antagonist series. SR 46349 potently inhibited serotonin-induced aggregation of rabbit
and human platelets (IC50 = 1 and 3.9 nM respectively) but had no effect on the action of other platelet aggregating
agents. SR 46349 was 118 and 25 times more potent than ketanserin against 5-HT + epinephrine-induced
aggregation of rabbit and human platelets respectively.
A single per os administration of SR 46349 (1 mg/kg) resulted in a strong inhibition
of 5-HT + epinephrine-induced platelet aggregation in the rabbit as measured ex vivo
(67% inhibition, 6 h after the administration). Intravenous or oral administration
of SR 46346 inhibited in a dose-dependent manner venous thrombosis induced by ligature
of the jugular vein of rabbits whose blood was made hypercoagulable by i.v. administration
of tissue thromboplastin. The doses of SR 46349 which inhibited 50% of thrombus formation
were 1.5 ± 0.8 mg/kg and 17 ± 0.5 mg/kg after i.v. or oral administration respectively.
When given i.v. to rabbits, SR 46349 exhibited a dose-dependent antithrombotic effect
in an arterio-venous shunt model. Significant increase of the bleeding time was observed
after the i.v. administration of 5 mg/kg of SR 46349 (3-fold increase). In dogs, SR
46349 inhibited cyclic coronary artery blood flow variations, complete abolition of
CFVs being achieved after the i.v. administration of 0.5 mg/kg.
In conclusion, SR 46349 is a highly potent, selective antagonist of serotonin in vitro
and is to be considered as a potent, orally active antithrombotic agent.
