SYNTHESIS OF 3-SUBSTITUTED AND 5'-SUBSTITUTED FLAVONE-8-CARBOXYLIC ACIDS AS 3-ARMED LEUKOTRIENE CYSLT(1) RECEPTOR ANTAGONISTS

Molecular modelling of leukotriene CysLT(1) receptor antagonists have suggested that in addition to the two binding sites for a lipophilic a nd an acidic group, the receptor has a 'third pocket' to accommodate ' three-armed' ligands such as montelukast 1. Based on the most rigid Cy sLT(1) receptor antagonist 3'-[2-(2-quinolinyl)ethenyl]flavone-8-carbo xylic acid 2, we have synthesised 3- and 5'-substituted flavone deriva tives to probe this additional binding pocket. Introduction of large s ubstituents, e.g. 2-quinolinyl-methoxy, to the C5' position of the fla vone skeleton abolished the CysLT(1) receptor affinity whereas the sam e modification at the C3 position yielded a potent CysLT antagonist. T his observation implies that the third binding pocket of the receptor has considerable steric tolerance, probably corresponding to the subst ituents at C3 of the flavone skeleton. Further modification by introdu cing a C3 substituent containing a basic nitrogen resulted in compound 6g with potent H-1 antihistaminic activity although the CysLT(1) anta gonistic activity was much reduced. Further study on the CysLT(1) rece ptor recognition of three armed antagonists may facilitate the design of more effective antiasthmatic agents, e.g. dual antagonists of hista mine H-1 and leukotriene CysLT(1) receptors. (C) Elsevier, Paris.