Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat |
| |
Authors: | S Stürzebecher M Haberey B Müller E Schillinger G Schrder W Skuballa G Stock H Vorbrüggen W Witt |
| |
Institution: | S. Stürzebecher, M. Haberey, B. Müller, E. Schillinger, G. Schröder, W. Skuballa, G. Stock, H. Vorbrüggen,W. Witt, |
| |
Abstract: | 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-memetics with a potency equal or even superior to PGI2.The 3-oxa-analogue was found to be stabilized against β-oxidation, a main metabolic degradation step also for chemically stable PGI2-analogues. The compound is orally available and displays a long duration of 4,5 – 48 h of antiaggregatory and hypotensive action. The 3-oxa-analogue inhibits ADP-induced platelet aggregation with an IC50 of 3.0 nM. Following intravenous application the 3-oxa-analogue lowers diastolic blood pressure in a dose dependent manner, the ED20 being 0.1 – 0.2 μg/kg after injection and ≤ 0.05 μg/kg/min after infusion respectively. In vivo platelet aggregation is inhibited after i.v. infusion of the 3-oxa-analogue with an IC50 of 0.037 μg/kg/min. As compared to Iloprost, the 3-oxa-analogue is 5 – 12 fold more potent with respect to in vivo hypotensive and anti-aggregatory effects.The results of the present studies indicate that the 3-oxa-analogue has a pharmacological profile comparable to prostacyclin (PGI2) and Iloprost. Due to the fact that the 3-oxa-analogue is chemically and metabolically stable, long term oral treatment can be achieved in clinical conditions in which PGI2 and Iloprost have already been shown to be therapeutically useful principles. |
| |
Keywords: | |
本文献已被 ScienceDirect 等数据库收录! |
|