Synthesis and structure-activity relationships of 5-phenylthiophenecarboxylic acid derivatives as antirheumatic agents.
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.
Noguchi
Toshiya
T
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 403, Yoshino-cho, 1-chome, Kita-ku, Saitama-city, 330-8530 Saitama, Japan. t.noguchi@po.rd.taisho.co.jp
Hasegawa
Masahiro
M
Tomisawa
Kazuyuki
K
Mitsukuchi
Morihiro
M
D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D010666:Phenylpropionates / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects
D018501:Antirheumatic Agents; D007375:Interleukin-1; D010666:Phenylpropionates; D013876:Thiophenes; C078547:esonarimod