7,8-Dialkoxy-substituted pyrimido

SAR summary Ethyl esters of 7,8-dialkoxy substituted pyrimido[4,5-b]-quinoline-2-carboxyIic acids display optimal potency. The dimethoxy (XXXV), diethoxy (XLVI) and the methoxy-ethoxy isomers (XLII and XLIII) are 80-400 times more potent than DSCC intravenously. Morever, in contrast to DSCC, these compounds are active orally, having EDso s of 1 mg/kg or less in the PCA procedure. 

Successive molecular modification of our original quinazoline-2-car-boxylic acid led to compounds displaying 5000-fold increases in potency. Several 7,8-dialkoxy substituted pyrimido 4,5-b]quinoline esters are 80 to 400 times as potent as DSCC intravenously, and, more importantly, have potent oral activity in the rat PCA test with ED,o s of 1 mg/kg or less. Comparison with other agents that display oral activity in this test shows that the pyrimido[4,5-b]quinoline series ranks among the most potent orally active inhibitors of mediator release reported to date. 

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