[The inhibitory activities of 480156-S and its related compounds on prostaglandin synthetase].
The inhibitory activities of 2-arylpropionic acids on prostaglandin synthetase were in the order of: Flurbiprofen (ID50, 0.10 microM) greater than Indomethacin (0.28 microM) greater than Ketoprofen (0.34 microM) greater than Naproxen (2.5 microM) greater than 480156-S (6.0 microM) greater than Ibuprofen (6.5 microM) greater than Benoxaprofen (47.9 microM). The S(+)-enantiomers had 15-300 times higher inhibitory activities than the corresponding R(-)-enantiomers. 2-Phenylpropionic acid and the metabolites of 480156-S (M-I, M-II and M-III) did not show any inhibitory activity on prostaglandin synthetase. Therefore, the presence of a hydrophobic substituent group, such as thiazolyloxy, on the benzene ring of 2-phenylpropionic acid is essential for the inhibition of prostaglandin synthetase, and the compound with the para substituent showed the highest inhibitory activity. The substituent groups also influence the inhibitory activity. Thiazolylamino (compound No. 320) and 3-methyl-4-thiazolin-2-ylidenamino (229) showed higher inhibitory activity than thiazolyloxy (156), and N-methyl-N-thiazol-2-ylamino (185) showed the lowest activity. The placement of a fluoro atom at the 3-position or two chloro atoms at the 3,5-positions of the benzene ring increased the inhibitory activity of the prostaglandin synthetase, but this did not necessarily occur with the placement of a chloro atom at the 3-position. Inhibitory activities of 480156-S-related compounds against prostaglandin synthetase showed a good correlation with their anti-inflammatory activities, but did not correlate with their analgesic activities.
Yamaguchi
T
T
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Hirose
K
K
Nakamura
Y
Y
Sugeno
K
K
D000700:Analgesics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003864:Depression, Chemical; D005260:Female; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010666:Phenylpropionates; D011453:Prostaglandins; C041431:480156-S