Synthesis and structure-activity relationships of carboxyflavones as structurally rigid CysLT1 (LTD4) receptor antagonists

Journal of Medicinal Chemistry
M E ZwaagstraM Q Zhang

Abstract

The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT1 receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [3H]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT1 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 moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT1 affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity ...Continue Reading

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Citations

Jan 1, 2010·Acta Crystallographica. Section E, Structure Reports Online·Yu-Hua LongHan-Mei Zhang
Jun 30, 2001·Japanese Journal of Pharmacology·T TakizawaH Timmerman
Jul 16, 2014·European Journal of Medicinal Chemistry·Manjinder SinghOm Silakari
Feb 9, 2012·Chemistry, an Asian Journal·Tanmoy ChandaMaya Shankar Singh
Sep 30, 2010·Natural Product Reports·Alok Kumar Verma, Ram Pratap
Nov 28, 2013·Organic & Biomolecular Chemistry·James McNultyLorraine Jones-Brando
Nov 25, 2003·The Journal of Organic Chemistry·Sanjay S PalimkarKumar V Srinivasan
Apr 28, 2004·Bioorganic & Medicinal Chemistry·Teshome Leta AboyePrasad V Bharatam

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