Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Bioorg Med Chem Lett ; 21(9): 2665-9, 2011 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-21273063

RESUMEN

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC(50)=3600 nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined with the termini SAR optimizations yielded a potent and highly selective agonist suitable for further preclinical development (58).


Asunto(s)
Diabetes Mellitus Tipo 2 , Diseño de Fármacos , Receptores Acoplados a Proteínas G/agonistas , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Éteres Cíclicos/síntesis química , Éteres Cíclicos/química , Humanos , Ratones , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad
2.
Proc Natl Acad Sci U S A ; 105(14): 5337-42, 2008 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-18391212

RESUMEN

The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-A resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.


Asunto(s)
Proteínas de Unión al ADN/agonistas , Proteínas de Unión al ADN/química , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/química , Esteroides/química , Factores de Transcripción/agonistas , Factores de Transcripción/química , Sitios de Unión , Ácidos Carboxílicos , Cristalografía por Rayos X , Humanos , Ligandos , Unión Proteica , Relación Estructura-Actividad , Especificidad por Sustrato
3.
Bioorg Med Chem Lett ; 16(11): 3055-60, 2006 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-16529931

RESUMEN

Counterscreening compounds from a Merck PPAR program discovered lead 1, as a nanomolar LXR/PPAR dual agonist. SAR optimization developed a series of heterocyclic LXR agonists having excellent selectivity over all PPAR isoforms and possessing high LXR affinity and strong in vivo potency.


Asunto(s)
Proteínas de Unión al ADN/agonistas , Diseño de Fármacos , Receptores Citoplasmáticos y Nucleares/agonistas , Ácidos/química , Aminación , Compuestos de Anilina/química , Animales , HDL-Colesterol/sangre , Ciclización , Indoles/química , Receptores X del Hígado , Ratones , Estructura Molecular , Receptores Nucleares Huérfanos , Relación Estructura-Actividad
4.
Biochem Pharmacol ; 71(4): 453-63, 2006 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-16325781

RESUMEN

Liver X receptor (LXR) alpha and LXRbeta are closely related nuclear receptors that respond to elevated levels of intracellular cholesterol by enhancing transcription of genes that control cholesterol efflux and fatty acid biosynthesis. The consequences of inactivation of either LXR isoform have been thoroughly studied, as have the effects of simultaneous activation of both LXRalpha and LXRbeta by synthetic compounds. We here describe the effects of selective activation of LXRalpha or LXRbeta on lipid metabolism. This was accomplished by treating mice genetically deficient in either LXRalpha or LXRbeta with an agonist with equal potency for both isoforms (Compound B) or a synthetic agonist selective for LXRalpha (Compound A). We also determined the effect of these agonists on gene expression and cholesterol efflux in peritoneal macrophages derived from wild-type and knockout mice. Both compounds raised HDL-cholesterol and increased liver triglycerides in wild-type mice; in contrast, in mice deficient in LXRalpha, Compound B increased HDL-cholesterol but did not cause hepatic steatosis. Compound B induced ATP-binding cassette transporter (ABC) A1 expression and stimulated cholesterol efflux in macrophages from both LXRalpha and LXRbeta-deficient mice. Our data lend further experimental support to the hypothesis that LXRbeta-selective agonists may raise HDL-cholesterol and stimulate macrophage cholesterol efflux without causing liver triglyceride accumulation.


Asunto(s)
Proteínas de Unión al ADN/agonistas , Metabolismo de los Lípidos/fisiología , Receptores Citoplasmáticos y Nucleares/agonistas , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Administración Oral , Animales , Colesterol/metabolismo , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , AMP Cíclico/farmacología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Isoxazoles/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Receptores X del Hígado , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Receptores Nucleares Huérfanos , Compuestos de Fenilurea/farmacología , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Pirazinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismo
5.
Bioorg Med Chem Lett ; 13(19): 3185-90, 2003 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-12951090

RESUMEN

A new class of O-arylmandelic acid PPAR agonists show excellent anti-hyperglycemic efficacy in a db/db mouse model of DM2. These PPARalpha-weighted agonists do not show the typical PPARgamma associated side effects of BAT proliferation and cardiac hypertrophy in a rat tolerability assay.


Asunto(s)
Ácidos Mandélicos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Animales , Ácidos Mandélicos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo
6.
Bioorg Med Chem Lett ; 13(5): 931-5, 2003 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-12617924

RESUMEN

A series of amphipathic 3-phenylbenzisoxazoles were found to be potent agonists of human PPARalpha, gamma and delta. The optimization of acid proximal structure for in vitro and in vivo potency is described. Results of po dosed efficacy studies in the db/db mouse model of type 2 diabetes showed efficacy equal or superior to Rosiglitazone in correcting hyperglycemia and hypertriglyceridemia. Good functional receptor selectivity for PPARalpha and gamma over PPARdelta can be obtained.


Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas , Factores de Transcripción/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Células COS , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Isoxazoles/farmacocinética , Ratones , Ratones Mutantes , Proteínas Nucleares/agonistas , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Rosiglitazona , Tiazoles/farmacocinética , Tiazoles/farmacología , Factores de Transcripción/metabolismo
7.
Mol Endocrinol ; 17(4): 662-76, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12554792

RESUMEN

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.


Asunto(s)
Indoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/química , Sulfuros/farmacología , Factores de Transcripción/agonistas , Factores de Transcripción/química , Adipocitos/efectos de los fármacos , Adipocitos/fisiología , Tejido Adiposo/efectos de los fármacos , Animales , Cardiomegalia/inducido químicamente , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Hiperglucemia/tratamiento farmacológico , Resistencia a la Insulina , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Proteica , Aumento de Peso/efectos de los fármacos
8.
Assay Drug Dev Technol ; 1(6): 777-87, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15090224

RESUMEN

Activation of liver X receptors (LXRs) induces reverse cholesterol transport and increases high-density lipoprotein cholesterol in vivo. Here, we describe novel, functional, homogeneous cell-based fluorescence resonance energy transfer assays for identifying agonists of LXRs using beta-lactamase as the reporter gene. Stable Chinese hamster ovary cell lines expressing LXRalpha-GAL4 or LXRbeta-GAL4 fusion proteins that regulate beta-lactamase transcription from upstream 7 x UAS GAL4 DNA binding sequences were generated and characterized. Synthetic and natural ligands of LXR dose-dependently activated the expression of beta-lactamase in a subtype-specific manner. These assays were used to demonstrate that a 1-pyridyl hydantoin small molecule LXR synthetic ligand specifically activates LXRalpha receptors. The beta-lactamase assays were optimized for cell density, dimethyl sulfoxide sensitivity, and time of agonist stimulation. Clonal LXRbeta-GAL4-beta-lactamase cells were miniaturized into an ultra high throughput (3456-well nanoplates) screening format.


Asunto(s)
Transferencia Resonante de Energía de Fluorescencia/métodos , Hígado/metabolismo , Miniaturización/métodos , Receptores Citoplasmáticos y Nucleares/agonistas , beta-Lactamasas/química , Animales , Benzoatos/química , Benzoatos/farmacología , Bencilaminas/química , Bencilaminas/farmacología , Células CHO , Cricetinae , Proteínas de Unión al ADN , Relación Dosis-Respuesta a Droga , Humanos , Receptores X del Hígado , Receptores Nucleares Huérfanos , Receptores Citoplasmáticos y Nucleares/metabolismo
9.
J Biol Chem ; 277(12): 10021-7, 2002 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-11790770

RESUMEN

The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 (formerly known as ABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRalpha (NR1H3) and LXRbeta (NR1H2). In transient transactivation assays, APD was approximately 1000-fold more potent, and yielded approximately 6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1 mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Abietanos , Colesterol/metabolismo , Colesterol/farmacología , Fenantrenos/química , Fenantrenos/metabolismo , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Transportador 1 de Casete de Unión a ATP , Transporte Biológico , Línea Celular , Células Cultivadas , Proteínas de Unión al ADN , Dimerización , Relación Dosis-Respuesta a Droga , Fibroblastos/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Humanos , Ligandos , Lipoproteínas HDL/metabolismo , Receptores X del Hígado , Macrófagos/metabolismo , Modelos Químicos , Receptores Nucleares Huérfanos , Fosfolípidos/metabolismo , Unión Proteica , Activación Transcripcional , Células Tumorales Cultivadas
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...