RESUMEN
Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.
Asunto(s)
Proteínas de Unión al ADN/agonistas , Indoles/química , Indoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Sitios de Unión , Línea Celular , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Receptores X del Hígado , Modelos Moleculares , Estructura Molecular , Receptores Nucleares Huérfanos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Relación Estructura-Actividad , Regulación hacia ArribaRESUMEN
Synthesis and structure-activity relationship of a series of 4-(2-aryl-cyclopropylamino)-quinoline-3-carbonitrile derivatives as EGFR inhibitors is described. Compounds 29 and 30 showed potent in vitro inhibitory activity in the enzymatic assay as well as in the functional cellular assay. They are moderately selective against other types of tyrosine kinases.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Nitrilos/química , Nitrilos/farmacología , Quinolinas/química , Quinolinas/farmacología , Inhibidores Enzimáticos/síntesis química , Nitrilos/síntesis química , Quinolinas/síntesis química , Relación Estructura-ActividadRESUMEN
A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described.
Asunto(s)
Proteínas de Unión al ADN/agonistas , Regulación de la Expresión Génica/efectos de los fármacos , Indoles/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/agonistas , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Línea Celular , Regulación de la Expresión Génica/fisiología , Humanos , Indoles/síntesis química , Receptores X del Hígado , Macrófagos/metabolismo , Modelos Químicos , Monocitos/citología , Receptores Nucleares Huérfanos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Relación Estructura-ActividadRESUMEN
A series of novel di- and trisubstituted 1,4-dihydroquinoxaline-2,3-diones (QXs) related to licostinel (Acea 1021) was synthesized and evaluated as antagonists for the glycine site of the N-methyl-D-asparate (NMDA) receptor. The in vitro potency of these antagonists was determined by displacement of the glycine site radioligand [(3)H]-5,7-dichlorokynurenic acid ([(3)H]DCKA) in rat brain cortical membranes. Structure-activity relationship studies indicate that a cyano group is a good replacement for the nitro group in the 5-position of licostinel while 5-carboxy, 5-ester, 5-ketone and 5-amide derivatives showed reduced potency. 5,6-Cyclized analogues of licostinel also showed significantly reduced potency. Among the trisubstituted QXs investigated, 5-cyano-6,7-dichloro QX and 5-cyano-7-chloro-6-methyl QX are the most potent with IC(50) values of 32 nM and 26 nM, respectively.