INHIBITION OF LEUKOTRIENE OMEGA-OXIDATION BY OMEGA-TRIFLUORO ANALOGS OF LEUKOTRIENES

ω-Oxidation with subsequent β-oxidation from the ω-end is the major pathway for inactivation and degradation of leukotrienes. Oxidative degradation of leukotriene E4 (LTE4), N-acetyl-LTE4, and LTB4 was inhibited by the ω-trifluoro analogs of LTE4, ω-trifluoro-LTE4 (ω-F3-LTE4), and (1,S,2R)-5-{3-[1-hydroxy-15, 15,15 - trifluoro - 2 - (2 - 1H - tetrazol - 5 - ylethylthio) pentadeca-3(E),5(Z)-dienyl]phenyl}-1H-tetrazole (LY 245769). The latter substance inhibited the oxidative degradation of LTE4 and N-acetyl-LTE4 in the rat in vivo by 50% at a dose of 7 μmol/kg body weight. In rat hepatocyte cultures both ω-trifluoro analogs interfered with the ω-oxidation of N-acetyl-LTE4 and LTB4 with IC50 values of about 4 μm. Both analogs inhibited the ω-hydroxylation in isolated rat liver microsomes with IC50 values between 16 and 37 μm. This inhibition is apparently competitive. In addition, in liver cytosol, the conversion of the ω-hydroxylated leukotrienes to ω-carboxy-LTE4 and ω-carboxy-LTB4 was inhibited by both compounds. ω-Trifluoro analogs of leukotrienes provide a new tool for interfering with the inactivation of leukotrienes in the ω-oxidation pathway. © 1990.