RESUMEN
A series of benzo[b]furan derivatives having a five-membered heterocyclic substituent at the 2-position were prepared from 2-(1-chloro-2-formylvinyl)benzo[b]furans (2) and 2-(4-alkylcarbamoylbuta-1,3-dienyl)benzo[b]furans. These 2-heterocyclic benzo[b]furans were evaluated for their cysteinyl leukotriene receptor (cysLT1, cysLT2) inhibitory activity. Several compounds showed moderate inhibition of calcium mobilization in HEK 293T-cysLT2 or CHO-cysLT1 cells.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacología , Receptores de Leucotrienos/metabolismo , Animales , Benzofuranos/síntesis química , Células CHO , Calcio/metabolismo , Cricetinae , Células HEK293 , Humanos , Antagonistas de Leucotrieno/síntesis químicaRESUMEN
The pharmacophore model (Hypo1) with a well prediction capacity for CysLT(1) antagonists was developed using Catalyst/HypoGen program. Virtual screening against an in-house database consisted of carboxylated chalcones using Hypo1 was performed. Retrieved hits 26a, 26b, 27a, and 27b were synthesized and biological evaluated, the results of which demonstrated that these compounds showed moderate to good CysLT(1) antagonistic activities. This study indicated that the generated model (Hypo1) is a reliable and useful tool in lead optimization for novel CysLT(1) antagonists.
Asunto(s)
Chalcona/química , Antagonistas de Leucotrieno/síntesis química , Receptores de Leucotrienos/química , Línea Celular Tumoral , Chalcona/síntesis química , Chalcona/farmacología , Bases de Datos Factuales , Evaluación Preclínica de Medicamentos , Humanos , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacología , Modelos Moleculares , Receptores de Leucotrienos/metabolismoRESUMEN
The syntheses of (2E)-2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl) prop-2-enoic acid (VUFB 20609) and racemic 2-methyl-3-(4-([4-(quinolin-2-ylmethoxy) phenyl]sulfanyl)phenyl)propanoic acid (VUFB 20584) as new potential antileukotrienic drugs are described. Due to a low reactivity of the 4-substituted aryl bromides (coupling of the 4-substituted aryl bromides do not provide an activating functional group with 4-methoxybenzene-1-thiol), special conditions, in particular specific heterogeneous copper catalysts, were used. Catalytic hydrogenation of the conjugated double bond on Pd/C in the presence of the sulfanyl group is discussed. In-vitro cytotoxicity testing was performed using a microplate colorimetric acid phosphatase assay. Antiplatelet activity was evaluated using an in-vitro test in human platelet-rich plasma. Some substances inhibited arachidonic acid-induced platelet aggregation.
Asunto(s)
Antagonistas de Leucotrieno/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Quinolinas/síntesis química , Sulfuros/síntesis química , Ácido Araquidónico/antagonistas & inhibidores , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Hidrogenación , Antagonistas de Leucotrieno/química , Antagonistas de Leucotrieno/farmacología , Estructura Molecular , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Quinolinas/química , Quinolinas/farmacología , Estereoisomerismo , Sulfuros/química , Sulfuros/farmacologíaRESUMEN
Exploration of the indole nitrogen region of Zafirlukast (1) has uncovered a potent series of cysteinyl leukotriene D4 (LTD4) antagonists. These studies showed that a variety of functionality could be incorporated in this region of the molecule without sacrificing potency. Efforts to exploit this site in order to improve oral efficacy are discussed.