Antithrombotic Activity of SR 46349, a Novel, Potent and Selective 5-HT2 Receptor Antagonist

Abstract

SummarySR 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.

APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology

“…Whereas APD791 had no effect on ADP-induced aggregation per se, it was a potent inhibitor of 5-HT-mediated amplification. Similar results have been reported for other less selective 5-HT 2A antagonists including ketanserin, sarpogrelate (M-1), R-96544, SR 46349, and AR246686 (Van Nueten et al, 1981;Herbert et al, 1993;Ogawa et al, 2002;Adams et al, 2008). The IC 50 of APD791 inhibition of human platelet aggregation (8.7 nM) was consistent with its K i for the human 5-HT 2A receptor (4.9 nM).…”

“…In conclusion, the present study demonstrates that APD791 is a potent, selective, and orally available 5-HT 2A receptor antagonist, and suggests that clinical evaluation of this drug is warranted because this profile offers potential improvements over previously described 5-HT 2A receptor antagonists (Van Nueten et al, 1981;Herbert et al, 1993;Ogawa et al, 2002). The combined inhibition of 5-HT-mediated thrombosis, vasoconstriction, and smooth muscle cell proliferation by APD791 could provide unique benefits for the treatment of thrombotic disease.…”

Effect of 5‐HT2A receptor antagonists on human platelet activation in blood exposed to physiologic stimuli and atherosclerotic plaque

“…This is in contrast to the recent study and the previous studies performed in dogs, which reported, in the absence of exogenous 5-HT, inhibition by 5-HT 2A receptor antagonists on platelets in vivo and in vitro [3,16,17]. Platelet inhibition in the absence of exogenous 5-HT has also been observed in other species [11,12,14,15].…”

“…A short survey of the literature shows that 5-HT 2A receptor antagonists have unequivocally been shown to inhibit 5-HT-potentiated platelet aggregation of PRP in humans and many other species in vitro and ex vivo [3,6,8,11,12] and 5-HT-stimulated thrombus formation in mice in vivo [13]. There are also animal studies reporting inhibition of aggregation induced by physiologic platelet stimuli (collagen, thrombin, ADP, and epinephrine) by 5-HT 2A receptor antagonists in vitro and ex vivo, and in thrombosis models in vivo, particularly in the Folts model of coronary occlusion in the dog [3,11,12,[14][15][16][17]. However, the results in humans are conflicting [5,[18][19][20].…”

Platelet Function and Pharmacology of Antiplatelet Drugs

“…However, inhibitors of these receptors have been generally disappointing in the context of arteri al thrombosis, although antagonists to serotonin receptors have proved effective in experimental animal models of thrombosis [21]. Although the search is on for the optimal inhibitor of arterial thrombosis, it should not be forgotten that combinations of inhibitors may be more efficient than the individual compounds alone.…”