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 (...

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Bibliographic Details
Published inJournal of pharmacy and pharmacology Vol. 33; no. 1; p. 29
Main Authors Tamura, S, Kuzuna, S, Kawai, K
Format Journal Article
LanguageEnglish
Published England 01.01.1981
Subjects
Animals
Anti-Inflammatory Agents - pharmacology
Cyclooxygenase Inhibitors
Dose-Response Relationship, Drug
Guinea Pigs
Indans - pharmacology
Indenes - pharmacology
Male
Molecular Conformation
Prostaglandin Antagonists - pharmacology
Prostaglandins - biosynthesis
Rabbits
Rats
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-3573
DOI:10.1111/j.2042-7158.1981.tb13696.x