Pharmacodynamics and antithrombotic effects after intravenous administration of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate.
The antiplatelet and antithrombotic activities of LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) a novel thromboxane A2 (TXA2) receptor antagonist were examined after intravenous administration. The correlation between LCB 2853 plasma concentration and ex vivo inhibition of arachidonic acid-induced aggregation was observed in rats, for 4 h, as long as LCB 2853 was detected in plasma by HPLC analysis. Pharmacokinetic parameters were determined. The antithrombotic activity was tested in arterial and venous thrombosis models. In dog coronary stenosis, LCB 2853 shown a very high efficacy (ED50 = 7.2 micrograms/kg), whereas acetylsalicylic acid (ASA) was only active at 3.2 mg/kg and ticlopidine was ineffective at 12.8 mg/kg. In rat venous thrombosis induced by combination of venous injury and blood stasis, perfused LCB 2853 decreased the weight of thrombi in a dose related manner (ED50 = 220 micrograms/kg/min). In a comparative study, at 250 micrograms/kg/min, ticlopidine was less potent and ASA failed to show any protection. The potent immediate efficacy of LCB 2853 and the advantageous comparisons with ASA (which was ineffective in some models) or ticlopidine (which needs metabolization lag time) observed in many models suggest that this compound may have beneficial effects in patients with TXA2-associated disturbances.
Depin
J C
JC
Lipha S.A., Research and Development Centre, Lyon, France.
Vigié
A
A
Chavernac
G
G
Rousselot
C
C
Lardy
C
C
Guerrier
D
D
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003328:Coronary Thrombosis / Q000517:prevention & control; D004285:Dogs; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D010648:Phenylacetates / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013924:Thrombophlebitis / Q000517:prevention & control; D013929:Thromboxane B2 / Q000378:metabolism*
D005343:Fibrinolytic Agents; D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013449:Sulfonamides; C091835:LCB 2853; D013929:Thromboxane B2