Substituted Chromenes As Potent, Orally Active 5-Lipoxygenase Inhibitors

A series of chromene derivatives was synthesized and evaluated for their in vitro and ex vivo 5-lipoxygenase (5-LO) inhibitory activity. These compounds were prepared by condensation of appropriate salicyl aldehydes with alpha,beta-unsaturated carbonyl compounds, followed by transformation to the corresponding hydroxamic acids or N-hydroxyureas. Placement of phenoxy or p-fluorophenoxy substituents at the 6 position of 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 other hand, replacement of the hydroxamic acid function with N-hydroxyurea yielded potent and long-lasting 5-LO inhibitors in the dog model. In most cases, the oral efficacy of the chromene N-hydroxyureas correlated very well with their in vitro activity. Compounds 43 (CGS 23885) and 55 (CGS 24891) are among the most potent inhibitors prepared, showing IC50 values of 48 and 51 nM, respectively. The values for the duration of action (DA) for compounds 43 and 55 are 21 and 20 h, respectively, following intravenous (iv) administration of 1.0 mg/kg. In the oral (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 sustained maximal inhibition (>95%) at earlier time points. The oral ED50 values of 43 and 55 in the ex vivo dog model are 0.23 and 0.23 mg/kg, respectively, at 6.0 h, and 2.37 and 1.63 mg/kg, respectively, at 24 h. Compound 43, which inhibits sheep seminal vesicle cyclooxygenase (CO) with an IC50 value of 36 muM, was shown to be a selective 5-lipoxygenase inhibitor in the ex vivo study. These compounds compare favorably with zileuton (A-64077) in all the parameters examined.