9,11-Epoxy-9-homo-14-thiaprost-5-enoic acid derivatives: potent thromboxane A2 antagonists.
A novel bicyclic prostaglandin analogue, (1S)-[1 alpha,2 alpha(Z),3 alpha,4 alpha]-7-[3-[(hexylthio)methyl]-7- oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid ((-)-10), and its cogeners were found to be potent antagonists at the TxA2 receptor. Compound (-)-10 was the only stereoisomer out of eight possible structures that was active. Thioether (-)-10 was 30-40-fold more potent than another TxA2 antagonist, BM 13.177, in inhibiting arachidonic acid (AA) induced aggregation of human platelet-rich plasma. Compound (-)-10 was effective (I50 = 0.5 +/- 0.4 microM) in inhibiting 9,11-azo-PGH2-induced (0.1 microgram/mL) contraction of guinea pig tracheal spirals. The bronchoconstriction in anesthetized guinea pigs induced by AA was also effectively antagonized by (-)-10 (1 mg/kg, iv); however, in this assay (-)-10 exhibited some direct agonist activity. Radioligand binding studies in washed (human) platelets revealed that (-)-10 is one of the most potent ligands for the PGH2/TxA2 receptor yet described (Kd = 1.6 +/- 0.4 nM).
Hall
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Department of Chemistry, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
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Harris
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Hedberg
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Ogletree
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D000818:Animals; D001980:Bronchi / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011449:Prostaglandin Endoperoxides / Q000494:pharmacology*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D010975:Platelet Aggregation Inhibitors; D011449:Prostaglandin Endoperoxides; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C059396:7-(3-((hexylthio)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid, (+)-isomer; D013928:Thromboxane A2