6,9-DEEPOXY-6,9-(PHENYLIMINO)-DELTA-6,8-PROSTAGLANDIN-I1, (U-60,257), A NEW INHIBITOR OF LEUKOTRIENE C-SYNTHESIS AND D-SYNTHESIS - INVITRO STUDIES

Google Scholar
  • 1 January 1982
    • journal article
    • research article
    • Vol. 23  (5) , 759-771
Abstract
Addition of the Ca ionophore, A 23187 [calcimycin], and cysteine to isolated mononuclear cells from rat peritoneal washings causes a marked increase in the formation of thromboxane [Tx] B2 along with the formation of leukotrienes C and D (LT). The formation of LT in this system was inhibited by 6,9-deepoxy-6,9-(phenylimino)-.DELTA.6,8-prostaglandin [PG] I1, U-60,257, or its methyl ester, U-56,467, (ID50 4.6 and 0.31 .mu.M, respectively). There was no inhibition of TxB2 formation. By contrast, 2 structurally-related compounds, PGI2 and its stable analog, 6- .beta.-PGI1, did not affect the formation of either LT 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 .mu.M), 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 in U-60,257-treated incubations.