Hydroxyindole derivatives as inhibitors of IL-1 generation. I. Synthesis and pharmacological activities of (E)-3-(4-hydroxy-5-methoxyindole-7-yl)-2-methylpropenoic acid derivatives

Article abstract of DOI:10.1016/0223-5234(96)88224-9

A series of (E)-3-(4-hydroxy-5-methoxyindole-7-yl)-2-methylpropenoic acids was prepared and the inhibitory activities of its members on IL-1 generation were evaluated in an in vivo system using the rat caboxymethyl cellulose-lipopolysaccharide (CMS-LPS) air-pouch model.Many compounds in this new series were found to be inhibitors of IL-1 generation.Structure-activity relationships indicated that a methyl substituent at the 1- and 3-positions on the indole ring are important for activity and that a 3,4,5-trimethoxy-substituted 2-phenyl group on the indole ring is suitable to give compounds exhibiting inhibition after oral administration.Among the compounds evaluated, (E)-3-<1,3-dimethyl-4-hydroxy-5-methoxy-2-(3,4,5-trimethoxyphenyl)indole-7-yl>-2-methylpropenoic acid (15m), which inhibited IL-1 generation by human monocytes stimulated with various reagents such as LPS, opsonized zymosan and immune complexes, showed inhibitory activity in the rat CMC-LPS model after oral administration. hydroxyindole derivative/ inhibitor of IL-1 generation/ rat CMC-LPS air-pouch model