3,4-Dihydro-2H-1-benzopyran-2-carboxylic Acids and Related Compounds as Leukotriene Antagonists

Article abstract of DOI:10.1021/jm00128a028

Evaluation of a series of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acids linked to the 2-hydroxyacetophenone pharmacophore present in the standard peptidoleukotriene antagonist FPL 55712 (1) has led to the discovery of Ro 23-3544 (7), an antagonist possessing greater potency and duration of action vs LTD₄ than the standard (aerosol route of administration, guinea pig bronchoconstriction model).Interestingly, this compound also potently inhibited bronchoconstriction induced by LTB₄ whereas 1 did not.Attempts to establish structure-activity relationships in this series involved modifications in the 2-hydroxyacetophenone moiety, the linking chain, and the chroman system.All variations produced analogues which were either inactive or possessed reduced potency relative to acid 7.Optical resolution of 7 was achieved by two methods.Absolute configurations of the enantiomers were determined via X-ray crystallographic analyses of an intermediate as well as a salt of the S enantiomer.Although the enantiommers exhibited similar potencies in in vitro assays and in vivo when administered intravenously, significant differences were observed in the guinea pig bronchoconstriction model vs LTC₄ and LTD₄ when administered by the aerosol route (S antipode 15-fold more potent).The properties of 7 have been compared with several recently reported leukotriene antagonists.