Synthesis and structure-activity relationships of anti-inflammatory 9,10-dihydro-9-oxo-2-acridine-alkanoic acids and 4-(2-carboxyphenyl)aminobenzenealkanoic acids.
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 microM, respectively. The inhibition observed for the control drug, naproxen, was 24 microM.
Taraporewala
I B
IB
Department of Chemistry, Philadelphia College of Pharmacy and Science, PA 19104.
Kauffman
J M
JM
D000166:Acridines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002351:Carrageenan; D055598:Chemical Phenomena; D002621:Chemistry; D016861:Cyclooxygenase Inhibitors; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051381:Rats; D013025:Glycine max / Q000201:enzymology; D013329:Structure-Activity Relationship
D000166:Acridines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D002264:Carboxylic Acids; D016861:Cyclooxygenase Inhibitors; D002351:Carrageenan