Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat

摘要: A novel carbacyclin derivative (16S)-13,14-dehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro- 6a- carbaprostaglandin-I2 (3-oxa-analogue) has been synthesized in order to find chemically and metabolically stable prostacyclin-mimetics with a potency equal or even superior PGI2. The 3-oxa-analogue was found be stabilized against beta-oxidation, main metabolic degradation step also for PGI2-analogues. compound is orally available displays long duration of 4.5-48 h antiaggregatory hypotensive action. inhibits ADP-induced platelet aggregation an IC50 3.0 nM. Following intravenous application the lowers diastolic blood pressure dose dependent manner, ED20 being 0.1-0.2 micrograms/kg after injection less than 0.05 micrograms/kg/min infusion respectively. In vivo inhibited i.v. 0.037 micrograms/kg/min. As compared Iloprost, 5-12 fold more potent respect anti-aggregatory effects. results present studies indicate that pharmacological profile comparable prostacyclin (PGI2) Iloprost. Due fact stable, term oral treatment can achieved clinical conditions which PGI2 Iloprost have already shown therapeutically useful principles.