Synthesis and Structure–Activity Relationships of Anti-inflammatory 9,lO-Dihydro-9-oxo-2-Acridine-alkanoic Acids and 4-(2-Carboxyphenyl)aminobenzenealkanoic Acids

Abstract

Eighteen test compounds, in three chemical series, were prepared as potential anti-inflammatory agents and evaluated by the rat hindpaw carrageenan-induced edema assay. The compounds, isosteric with known anti-inflammatory and antiallergic cyclo-oxygenase and lipoxygenase inhibitors, are 10-methyl-9, 10-dihydro-9-oxo-2-acridinealkanoic acids, 9, 10-dihydro-9-oxo-2-acridinealkanoic acids, and 4-(2-carboxyphenyl)aminobenzenealkanoic acids. Compounds within each of these series differ in the structure of the alkanoic acid side chain. Compounds containing the acetic acid and the branched 2-propionic acid side chain showed inhibition of carrageenan-induced edema. The activity of compounds with these side chains and the inactivity of those with carboxy, oxyacetic, thioacetic, and 3-propionic acid side chains is in accordance with the proposed template model of Appleton and Brown for the active site of cyclo-oxygenase, rather than with the alternative active site model proposed by Gund and Shen. One compound, (±)-2-[N-(2-carboxyphenyl)-4-aminophenyl]propionic acid (3c), showed edema inhibition at 50 mg/kg po, comparable to that of an equivalent dose level of (+)-naproxen. Compounds 4a and 5a, which contain a carboxylic acid side chain, exhibited inhibition of soybean 12-lipoxygenase with IC50 values of 17.2 and 8.4 μM, respectively. The inhibition observed for the control drug, naproxen, was 24 μM.