HYDROXYINDOLE DERIVATIVES AS INHIBITORS OF IL-1 GENERATION .2. SYNTHESIS AND PHARMACOLOGICAL ACTIVITIES OF (7-HYDROXY-6-METHOXYINDOLE-4-YL)-2-METHYLPROPENOIC ACID-DERIVATIVES

A series of (7-hydroxy-6-methoxyindole-4-yl)-2-methylpropenoic acid de rivatives was prepared and the inhibitory activities of its members on IL-1 generation were evaluated in an in vitro system using exudate ce lls from the rat carboxymethyl cellulose (CMC) induced air-pouch model . All the compounds in this new series were found to be inhibitors of IL-1 generation. In particular, the methoxy-substituted 2-phenyl compo unds 28d-f were the most potent inhibitors of IL-1 generation (eg, 28d : IC50 = 0.8 mu M). The compounds in this series also inhibited IL-1 a lpha and IL-1 beta generations in an in vitro system using human monoc ytes stimulated with LPS (eg, 28b: IC50 = 1.4 mu M (IL-1 alpha) and 0. 9 mu M (IL-1 beta)).