LG 6-101 and LG 6-102, two new propafenone-related antiarrhythmic agents with good oral activity in rats

Autor: W. R. Kukovetz, P. Dittrich, Thomas C. Wascher
Rok vydání: 1992
Předmět:
Zdroj: Naunyn-Schmiedeberg's Archives of Pharmacology. 345
ISSN: 1432-1912
0028-1298
DOI: 10.1007/bf00176627
Popis: LG 6-101 (1-[3-(2-methoxy-3-(2-methylpropyl-amino)-propoxy)-4-methyl-2-thienyl]-3-phenyl-l-propanon hydrochloride; MW 426.02) and LG 6-102 (2-(2-methoxy-3-propylamino-propoxy)-3-phenyl-propiophenon hydrochloride; MW: 391.92) are two new antiarrhythmic substances. They are structurally related to propafenone which is a widely used class Ic-antiarrhythmic drug. In man the oral bioavailability of propafenone is only about 5–40%. Therefore the development of compounds with similar mode of action but higher oral bioavailability seems to be meaningful. Both, LG 6-101 and LG 6-102 proved to be effective in isolated auricles and in experimental animals after intravenous administration. In the present study we tested the antiarrhythmic effects of LG 6-101 and LG 6-102 in rats after oral administration. Animals were treated with LG 6-101 (16, 32, 64, 128, 256 mg kg−1 bodyweight), LG 6-102 (4, 8, 16, 32, 64 mg kg−1 bodyweight) and propafenone (32, 64, 128, 256 mg kg−1 bodyweight) by gavage twice daily during 4 days. Both, LG 6-101 and LO 6-102 showed strong antiarrhythmic effects against arrhythmias induced on the fifth day by infusion of aconitine (10 μg kg−1 min−1). LG 6-102 was significantly more effective against cardiac arrest caused by infusion of aconitine (P ≤ 0.05) than LG 6-101. Both substances had good effects on the delay of ventricular premature beats. After administration of LG 6-101 (256 mg kg−1) maximum serum levels of 1298 ±1066 ng ml−1 (n = 10) and after administration of LG 6-102 (64 mg kg−1) maximum levels of 120±57 ng ml−1 (n = 10) were measured. Propafenone on the other hand had only negligible antiarrhythmic effects after the doses tested despite mean serum concentrations of up to 865 ± 167 ng ml−1 (n = 5) where reached after administration of 256 mg kg−1 bodyweight. Our results do not necessarily demonstrate an oral bioavailability of LG 6-101 and LG 6-102 superior to propafenone, but they confirm that these substances are potent antiarrhythmic drugs which at least in rats possess a better oral antiarrhythmic activity than propafenone.
Databáze: OpenAIRE
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