SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF CARBOXYLATED CHALCONES - A NOVEL SERIES OF CYSLT(1) (LTD(4)) RECEPTOR ANTAGONISTS

The synthesis and CysLT(1) antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)eth enyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are des cribed. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-posi tion. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1- methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lowe r activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl ]. The quinoline and chalcone moieties may be connected by either an e thenyl or a methoxy spacer. The acidic moiety at the chalcone B ring m ay be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- a nd 4-substituted chalcones. There are no general patterns to specify w hich substitution positions gave the most potent compounds. The series contains several potent CysLT(1) receptor antagonists, with K-D value s approaching the nanomolar range, as measured by the displacement of [H-3]LTD(4) from guinea pig lung membranes. Antagonism of LTD(4)-induc ed contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD( 4)-induced increase of vascular permeability in vivo are determined fo r chalcones with high CysLT(1) receptor affinities (K-D values below 0 .1 mu M) 4-(2-quinolinylmethoxy)-5'-(5--tetrazolyl)chalcone (14, VUF 4 819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.