title: Pharmacological profile of a novel carbacyclin derivative with high metabolic stability and oral activity in the rat.
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-mimetics with a potency equal or even superior to PGI2. The 3-oxa-analogue was found to be stabilized against beta-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 micrograms/kg after injection and less than or equal to 0.05 micrograms/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 micrograms/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.
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects*; D011464:Epoprostenol / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000031:analogs & derivatives; D006339:Heart Rate / Q000187:drug effects; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011982:Receptors, Prostaglandin / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D011982:Receptors, Prostaglandin; D011464:Epoprostenol; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; C043867:cicaprost