Inhibition of prostaglandin biosynthesis by clidanac and related compounds: structural and conformational requirements for PG synthetase inhibition.
The inhibition of prostaglandin (PG) biosynthesis by clidanac (6-chloro-5-cyclohexyl-1-indancarboxylic acid, TAI-284), its metabolites and some analogues has been examined using various microsomal preparations as enzyme source. Clidanac and some analogues were among the most potent inhibitors. The (+)-isomer of clidanac was shown to be 1000 times more potent than the (-)-isomer in inhibiting PG synthetase activity. The cis-3'-hydroxyl metabolite which retains anti-inflammatory activity comparable to that of clidanac had much less inhibitory activity. Structure-activity studies with clidanac analogues showed that the position of halogen substitution in 1-indancarboxylic acid is of considerable significance for the conformational requirement for binding to the enzyme.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007189:Indans / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis*; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007189:Indans; D007192:Indenes; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; C059095:clidanac