Structure--activity relationships in a series of novel 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylic acid antiallergy agents.
A series of more than 50 new 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylic acid derivatives and related compounds with substituent variations at the 2, 3, and 5--9 positions was prepared and evaluated for antiallergy activity using the rat PCA assay. These compounds were obtained by the condensation of the appropriately substituted 2-aminoquinoline-3-carboxamides with dialkyl oxalates, followed by further chemical transformations. More than two-thirds of the compounds prepared exhibited intravenous activity ranging from 1 to 400 times disodium cromoglycate (DSCG). Structure--activity data suggest that the presence of a carboxylic acid moiety at the 2 position affords optimal potency and that esters are preferred for good oral absorption. Best oral activity, with ED50 values ranging from 0.3 to 3.0 mg/kg, was displayed by ethyl esters with methoxy and/or ethoxy groups at the 7 and 8 positions.
D000284:Administration, Oral; D000818:Animals; D001993:Bronchodilator Agents / Q000138:chemical synthesis; D004205:Cromolyn Sodium / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000097:blood / Q000276:immunology; D006967:Hypersensitivity / Q000188:drug therapy*; D007275:Injections, Intravenous; D008297:Male; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D001993:Bronchodilator Agents; D011804:Quinolines; D006632:Histamine; D004205:Cromolyn Sodium