Synthesis of 3- and 5'-substituted flavone-8-carboxylic acids as 'three-armed' leukotriene CysLT1 receptor antagonists

Article abstract of DOI:10.1016/S0223-5234(98)80034-2

Molecular modelling of leukotriene CysLT₁ receptor antagonists have suggested that in addition to the two binding sites for a lipophilic and an acidic group, the receptor has a 'third pocket' to accommodate 'three-armed' ligands such as montelukast 1. Based on the most rigid CysLT₁ receptor antagonist 3'-[2-(2-quinolinyl)ethenyl]flavone-8-carboxylic acid 2, we have synthesised 3- and 5'-substituted flavone derivatives to probe this additional binding pocket. Introduction of large substituents, e.g. 2-quinolinyl-methoxy, to the C5' position of the flavone skeleton abolished the CysLT₁ receptor affinity whereas the same modification at the C3 position yielded a potent CysLT₁ antagonist. This observation implies that the third binding pocket of the receptor has considerable steric tolerance, probably corresponding to the substituents at C3 of the flavone skeleton. Further modification by introducing a C3 substituent containing a basic nitrogen resulted in compound 6g with potent H₁ antihistaminic activity although the CysLT₁ antagonistic activity was much reduced. Further study on the CysLT₁ receptor recognition of three-armed antagonists may facilitate the design of more effective antiasthmatic agents, e.g. dual antagonists of histamine H₁ and leukotriene CysLT₁ receptors.