DuP-654

DuP 654 (2-benzyl-1-naphthol) is a topically active anti-inflammatory agent that was evaluated in phase II clinical trials as an anti-psoriatic agent. The compound is a potent 5-lipoxygenase inhibitor and exhibits inhibitory activity against lipopolysaccharide-stimulated release of interleukin-1 from human monocytes. DuP 654 cannot be used as a systemic anti-inflammatory compound due to its rapid and extensive metabolism. Fifteen analogs were synthesized in an attempt to block the systemic route(s) of metabolism. The compounds were evaluated (IP and PO) in the rat carrageenan paw edema inflammation model with plasma samples taken at 1, 2, 3, and 4 hours post-dose. Substitutions at the 4- and/or 8-positions on the naphthol, and/or on the benzyl group of the DuP 654 molecule were unsuccessful in achieving an analog which displayed both oral activity in the inflammatory model and high plasma levels without manifesting toxicity. The low plasma levels of some analogs may indicate poor absorption, high volume of distribution, or that the substitution did not inhibit the high hepatic "first-pass" metabolism observed with DuP 654. Other compounds not studied but similar in structure to DuP 654 may exhibit rapid and extensive metabolism.

The possible utility of DuP 654, a potent 5-lipoxygenase inhibitor, for treating human inflammatory skin disease was investigated in murine skin treated with 1.0 mg arachidonic acid (AA). When DuP 654 was applied to murine skin treated with AA, it inhibited the resulting inflammation and influx of cells. High performance liquid chromatography and radioimmunoassay analysis of lipid extracts from AA-treated ears indicated that the influx of polymorphonuclear leukocytes (PMN) was temporally preceded by an appearance of significant amounts of 5-HETE (6.7 ± 1.4 ng/ear) and Leukotriene B₄ LTB4 0.92 ± 0.2 ng/ear) when compared with extracts of untreated ears (5-HETE, 02 ± 0.3 ng/ear; LTB₄, < 0.1 ng/ear). The levels of the 5-lipoxygenase products were reduced by treatment with 10 µg/ear DuP 654. Lipid extracts from AA-treated ears contain chemotactic activity for human PMN and this chemotactic activity in the AA-treated ears could be reduced but not eliminated by immunosorption with anti-LTB4 antibodies coupled to protein A-agarose. The appearance of the chemotactic activity was inhibited by DuP 654. Taken together, these data suggest that DuP 654 may have utility in human inflammatory skin disease.