Inhibition by REV-5901 of leukotriene release from guinea-pig and human lung tissue in vitro

The 5-lipoxygenase inhibitor REV-5901 [α-pentyl-3-(2-quinolinylmethoxy)benzene-methanol] was evaluated for effects on mediator release in vitro from fragmented guinea-pig and human lung. In guinea-pig lung, REV-5901 inhibited the antigen-induced release of immunoreactive leukotriene D 4 (iLTD 4) with an ic 50 of 9.6 ± 2.9 μM and immunoreactive leukotriene B 4 (iLTB 4) with an ic 50 of 13.5 ± 2.2 μM. REV-5901 also inhibited the calcium ionophore-induced release of immunoreactive leukotrienes from human lung in vitro with ic 50 values of 11.7 ± 2.2 μM versus peptide leukotrienes and 10.0 ± 1.1 μM versus iLTB 4. The inhibition of release of iLTD 4 and iLTB 4 with similar ic 50 values suggests that REV-5901 acts by inhibiting 5-lipoxygenase in this system. At concentrations as high as 50 μM, REV-5901 did not inhibit the release of thromboxane B 2 (TxB 2), 6-keto-prostaglandin-F 1α (6-keto-PGF 1α), or histamine from either lung. The lack of effect on TxB 2 and 6-keto-PGF 1α indicates that REV-5901 did not inhibit phospholipase A 2, cyclooxygenase, or thromboxane synthetase. Inhibition of leukotriene release by REV-5901 could not be reversed by washing. Among various 5-lipoxygenase inhibitors, the order of potency for inhibition of iLTD 4 release from guinea-pig lung was AA-861 > REV-5901 > phenidone > nafazatrom > NDGA > BW755C. These findings suggest that REV-5901 is a selectve and relatively potent inhibitor of leukotriene release from lung tissue in vitro.