RESUMEN
We describe a practical and scalable route to compound (Z)-1, a selective CCK1 receptor antagonist. Notable features of this concise route are (1) a regioselective construction of the pyrazole core through the reaction of an aryl hydrazine and an elaborated acetylenic ketone, (2) a Tf2O/pyridine mediated Z-selective dehydration of an α-hydroxyester, and (3) a stereoselective hydrolysis. The sequence is high-yielding and amenable for large-scale synthesis.
Asunto(s)
Clorobencenos/síntesis química , Dioxoles/síntesis química , Dioxoles/farmacología , Hidrazinas/química , Propionatos/síntesis química , Pirazoles/química , Pirazoles/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Clorobencenos/química , Dioxoles/química , Hidrólisis , Cetonas/química , Estructura Molecular , Propionatos/química , Pirazoles/síntesis química , EstereoisomerismoRESUMEN
Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos Insaturados/administración & dosificación , Hipoglucemiantes/administración & dosificación , Obesidad/tratamiento farmacológico , Éteres Fenílicos/administración & dosificación , Receptores X Retinoide/agonistas , Tiazolidinedionas/administración & dosificación , Análisis de Varianza , Animales , Apolipoproteína A-I/genética , Apolipoproteína A-I/fisiología , Área Bajo la Curva , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Hipoglucemiantes/uso terapéutico , Ratones , Ratones Transgénicos , Obesidad/sangre , Obesidad/complicaciones , PPAR gamma/agonistas , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Receptores X Retinoide/metabolismo , Rosiglitazona , Estadísticas no Paramétricas , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Glándula Tiroides/efectos de los fármacos , Triglicéridos/sangreRESUMEN
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
Asunto(s)
Derivados del Benceno/química , Derivados del Benceno/farmacología , Caprilatos/química , Caprilatos/farmacología , Tiazolidinedionas , Alquenos/química , Alquenos/farmacología , Animales , Derivados del Benceno/síntesis química , Caprilatos/síntesis química , Línea Celular , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Sinergismo Farmacológico , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Ratones , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/antagonistas & inhibidores , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide , Rosiglitazona , Relación Estructura-Actividad , Tiazoles/farmacología , Tiroxina/sangre , Factores de Transcripción/agonistas , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Triglicéridos/sangreRESUMEN
Treatment of oxazole or 5-aryl oxazoles with i-PrMgCl smoothly generates the corresponding 2-Grignard reagents, which react with Weinreb amides to provide exclusively 2-acyl oxazole products.
Asunto(s)
Amidas/química , Magnesio/química , Oxazoles/química , Espectroscopía de Resonancia MagnéticaRESUMEN
An efficient method for the stereoselective synthesis of (Z)-alpha-arylacrylates is described. Treatment of alpha-hydroxyesters with triflic anhydride and pyridine at 0 degrees C followed by warming to room temperature afforded the corresponding (Z)-alpha-aryl-alpha,beta-unsaturated esters in very good yields and excellent stereoselectivity.
Asunto(s)
Ésteres/síntesis química , Deshidratación , Ésteres/química , Espectroscopía de Resonancia Magnética/métodos , Estructura Molecular , Sensibilidad y Especificidad , EstereoisomerismoRESUMEN
The synthesis and in vitro characterization of novel RXR-selective ligands possessing various substituted 1-benzofuran or 1-benzothiophene moieties are described.
Asunto(s)
Diseño de Fármacos , Receptores de Ácido Retinoico/metabolismo , Factores de Transcripción/metabolismo , Tretinoina/análogos & derivados , Tretinoina/metabolismo , Unión Proteica/fisiología , Receptores X Retinoide , Relación Estructura-ActividadRESUMEN
New RXR-selective modulators possessing a 6-fluoro trienoic acid moiety (6Z olefin) or a fluorinated/heterocyclic-substituted benzene core ring, were synthesized in an expedient and selective way. A subset of these compounds was evaluated for their metabolic properties (exposure in IRC male mice) and show a dramatic increase of exposure compared to our reference compound, 3 (LG101506).