(Piperidinylalkoxy)chromones: novel antihistamines with additional antagonistic activity against leukotriene D4.
A series of novel chromone derivatives, in which the chromone moiety is connected to a (diphenylmethylene)-, (diphenylmethyl)-, or (diphenylmethoxy)piperidine via an alkyloxy spacer, were synthesized as antiallergic and antiasthmatic agents. In addition to their potent antihistaminic activity, the compounds also inhibit contraction in guinea pig ileum induced by leukotriene D4. When analyzed by radioligand binding assays in guinea pig lung membranes, one of the compounds, 7-[[3-[4-(diphenylmethylene)piperidin-1- yl]propyl]oxy]-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran, showed dissociation constants (KD) of 5.62 nM and 2.34 microM for H1- and LTD4-receptors, respectively. In vivo at the dose of 10 mg/kg, the compound inhibited the histamine- and LTD4-induced increase of vascular permeability in guinea pigs by 95 and 30%, respectively. The inhibition of LTD4-induced increase in vascular permeability by the compound was increased to 56% when a dose of 50 mg/kg was employed. Similar to terfenadine, the compound does not readily occupy the brain H1-receptors when given intraperitoneally to mice, implying no sedating side effects.
Zhang
M Q
MQ
Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Amsterdam, The Netherlands.
Wada
Y
Y
Sato
F
F
Timmerman
H
H
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D002867:Chromones / Q000378:metabolism / Q000494:pharmacology*; D004336:Drug Antagonism; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D008168:Lung / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D011738:Pyrilamine / Q000037:antagonists & inhibitors / Q000378:metabolism
D002867:Chromones; D006634:Histamine H1 Antagonists; D017998:Leukotriene D4; D011738:Pyrilamine