N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides as orally active antiallergy agents

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Abstract
A series of N-(heterocyclic alkyl)pyrido[2,1-b]quinazoline-8-carboxamides were evaluated for their ability to antagonize slow-reacting substance of anaphylaxis (SRS-A) induced contractions of guinea pig ilea and to inhibit thromboxane synthase in vitro. The results indicated that those pyrido[2,1-b]quinazoline-8-carboxamides bearing a branched-chain alkyl moiety in the 2-position and a four to six atom linear chain between a 3- or 4-substituted pyridine or a 1-substituted imidazole ring and the carboxamide nitrogen atom showed the best combination of potencies in the two assays. Several of these compounds were found to be orally active inhibitors of LTE4-induced bronchoconstriction in the guinea pig and LTE4-induced skin wheal formation in the rat. One of the most potent analogues, 2-(1-methylethyl)-N-(1H-imidazol-1-ylbutyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxamide (36), was selected for extensive pharmacological investigation. It was found that this compound was not a specific inhibitor of LTE4-induced symptomatology, but exhibited more general activity by inhibiting bronchospasm in guinea pigs induced by LTC4, LTD4, PAF, and histamine and skin wheal formation in rats and guinea pigs induced by LTC4, LTD4, and PAF. In addition, 36 was orally active in the passive cutaneous anaphylaxis assay, suggesting that it also exhibits mediator release inhibitory activity. On the basis of the overall pharmacological profile of 36 and its closely related analogues, it was concluded that these compounds may be useful for the treatment of asthma.