SUBSTITUTED CHROMENES AS POTENT, ORALLY-ACTIVE 5-LIPOXYGENASE INHIBITORS

A series of chromene derivatives was synthesized and evaluated for the ir in vitro and ex vivo 5-lipoxygenase (5-LO) inhibitory activity. The se compounds were prepared by condensation of appropriate salicyl alde hydes with alpha,beta-unsaturated carbonyl compounds, followed by tran sformation to the corresponding hydroxamic acids or N-hydroxyureas. Pl acement of phenoxy or p-fluorophenoxy substituents at the 6 position o f the chromene ring led to a dramatic increase in the in vitro potency as demonstrated by the guinea pig PMN 5-LO assay. Chromene hydroxamic acids, in general, behaved poorly in the ex vivo dog model. On the ot her hand, replacement of the hydroxamic acid function with N-hydroxyur ea yielded potent and long-lasting 5-LO inhibitors in the dog model. I n most cases, the oral efficacy of the chromene N-hydroxyureas correla ted very well with their in vitro activity. Compounds 43 (CGS 23885) a nd 55 (CGS 24891) are among the most potent inhibitors prepared, showi ng IC50 values of 48 and 51 nM, respectively. The values for the durat ion of action (DA) for compounds 43 and 55 are 21 and 20 h, respective ly, following intravenous (iv) administration of 1.0 mg/kg. In the ora l (po) experiments, 43 and 55 have DA's of 14 and 15 h, respectively, at a 1.0 mg/kg dose. In both iv and po experiments, 43 and 55 showed s ustained maximal inhibition (>95%) at earlier time points. The oral ED 50 values of 43 and 55 in the ex vivo dog model are 0.23 and 0.23 mg/k g, respectively, at 6.0 h, and 2.37 and 1.63 mg/kg, respectively, at 2 4 h. Compound 43, which inhibits sheep seminal vesicle cyclooxygenase (CO) with an IC50 value of 36 muM, was shown to be a selective 5-lipox ygenase inhibitor in the ex vivo study. These compounds compare favora bly with zileuton (A-64077) in all the parameters examined.