title: Synthesis and structure-activity relationships of carboxylated chalcones: a novel series of CysLT1 (LTD4) receptor antagonists.
abstract: The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. 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-position. 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 lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.
authors.affiliation: Leiden/Amsterdam Centre for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Zwaagstra
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
authors.forename: M
authors.initials: M
authors.lastname: Tamura
authors.forename: T
authors.initials: T
authors.lastname: Tohma
authors.forename: Y
authors.initials: Y
authors.lastname: Wada
authors.forename: K
authors.initials: K
authors.lastname: Onogi
authors.forename: M Q
authors.initials: MQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002599:Chalcone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins; D009119:Muscle Contraction / Q000187:drug effects; D018077:Receptors, Leukotriene; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
chemical_list: D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D002599:Chalcone; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor