6,9-deepoxy-6,9,-(phenylimino)-delta 6,8-prostaglandin I1, (U-60,257), a new inhibitor of leukotriene C and D synthesis: in vitro studies.
Addition of the calcium inophore, A 23187, and cysteine to isolated mononuclear cells from rat peritoneal washings causes a marked increase in the formation of thromboxane B2 (TxB2) along with the formation of leukotrienes C and D (LT's). The formation of LT's in this system was inhibited by 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1, U-60,257, or its methyl ester, U-56,467, (ID50 4.6 and 0.31 microM, respectively). There was no inhibition of TxB2 formation. By contrast, two structurally-related compounds, PGI2 and its stable analog, 6-beta-PGI1, did not affect the formation of either LT's or TxB2. The inhibition of LT formation by U-60,257 was rapidly reversed after removal of this compound from the cells. U-60,257 did not inhibit the cyclooxygenase of human polymorphonuclear leukocytes. Nor did it inhibit formation of 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) in human platelets. On the other hand, U-60,257 inhibited glutathione S-transferase activity of rat basophil leukemia cells (ID50, 37 microM), suggesting that this compound may inhibit the last step in LTC biosynthesis. In addition to inhibiting LT synthesis, U-60,257 also appears to be a competitive inhibitor of the action of LT on the guinea pig ileum, although this inhibition requires a higher drug concentration than those ordinarily encountered during assay for LT's in U-60,257-treated incubations.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects; D011464:Epoprostenol / Q000494:pharmacology* / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D013189:SRS-A / Q000096:biosynthesis*; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors
D001095:Arachidonic Acids; D011453:Prostaglandins; D013189:SRS-A; D016718:Arachidonic Acid; D013929:Thromboxane B2; C035297:U 56467; D011464:Epoprostenol; C035296:piriprost