SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF CARBOXYFLAVONES AS STRUCTURALLY RIGID CYSLT(1) (LTD4) RECEPTOR ANTAGONISTS

The synthesis and CysLT(1) receptor affinities of a new series of high ly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinoli nyl)ethenyl]-substituted 6-, 7-, or 8-carboxylated flavones are descri bed. CysLT(1) receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [H-3]LTD4 from its receptor i n guinea pig lung membranes. Structure-affinity relationship studies s howed that the relative positions of the carboxylic acid and the quino line moiety were critical for CysLT(1) affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline mo iety may be connected to the flavone skeleton by an ethenyl or a metho xy linker, but the substitution position is important for high affinit y, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxy flavones are essentially inactive, whereas the 3'-substituted analogue s have submicromolar CysLT(1) affinity. Replacement of the quinoline b y other heteroaromates generally leads to decreased affinities, with t he phenyl and naphthyl analogues displaying only little or no affinity , while the 7-chloroquinoline analogue is comparable in activity to th e quinoline. Flavones having CysLT(1) receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD 4-induced contraction of guinea pig ileum in vitro. The IC50 values ra nged between 15 and 100 nM. Compound 5d -carboxy-6-chloro-3'-(2-quinol inylmethoxy)flavone, VUF 5087) was selected for further research becau se of its high potency in the functional assay. This series contains t he most rigid CysLT(1) receptor antagonists known to date, and they ar e useful in the development of a CysLT(1) antagonist model, which is d iscussed in the companion paper.