Synthesis and structure-activity relationships of 5-phenylthiophenecarboxylic acid derivatives as antirheumatic agents

Abstract 5-(Phenylthiophene)-3-carboxylic acid ( 2a ), a metabolite of esonarimod ( 1 ), which was developed as a new antirheumatic drug, was considered as a lead compound for new antirheumatic drugs. A new series of 2a derivatives were synthesized and their characteristic pharmacological effects, that is their antagonistic effect toward interleukin (IL)-1 in mice and the suppressive effect against adjuvant-induced arthritis (AIA) in rats, were evaluated and compared with those of 1 . The structure–activity relationships indicated that [5-(4-bromophenyl)-thiophen-3-yl]acetic acid ( 5d ), methyl [5-(4-chlorophenyl)-thiophen-3-yl]acetate ( 5h ), and methyl [5-(4-bromophenyl)-thiophen-3-yl]acetate ( 5i ) suppressed AIA more potently than 1 and all of the other synthesized compounds.