ABSTRACT
A series of substituted 11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acids were prepared and evaluated as antiallergy agents. Several analogues were orally active. 2-Methyl-11-oxo-11H-pyrido[2,1-b]quinoazoline-8-carboxylic acid (6) was superior to cromolyn sodium and doxantrazole orally and intravenously in the rat PCA test and a rat allergic bronchospasm model.
Subject(s)
Hypersensitivity/drug therapy , Quinazolines/chemical synthesis , Animals , Bronchial Spasm/drug therapy , Bronchial Spasm/immunology , Bronchial Spasm/physiopathology , Histamine Release/drug effects , In Vitro Techniques , Mast Cells/drug effects , Mast Cells/immunology , Passive Cutaneous Anaphylaxis/drug effects , Pulmonary Ventilation/drug effects , Quinazolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
After administering 14C-labeled 3-(hydroxymethyl)-8-methoxychromone to rats by gavage, plasma was found to contain unchanged compound and three unconjugated metabolites. These metabolites were identified as 3-carboxy-8-methoxychromone, 8-methoxychromone, and 2-hydroxy-3-methoxyactophenone. The plasma levels of all four labeled compounds were determined from 30 min to 48 hr after drug administration. Only the levels of 3-(hydroxymethyl)-8-methoxychromone and 3-carboxy-8-methoxychromone correlated with the expression of antiallergy activity in the rat, and only these compounds were found to be active in vivo. However, a test system for the inhibition of anaphylactic histamine release in vitro showed activity only for 3-carboxy-8-methoxychromone.
