RESUMEN
2-Aminoimidazoles represent useful synthons for incorporation into medicinal compounds. They provide hydrogen bonding loci, water solubilizing properties and convenient handles for further synthetic elaboration. The rapid and facile generation of diverse 2-aminoimidazoles via tandem addition cyclization reaction of vinyl azides and cyanamide has been investigated. These reactions proceeded through either thermal or photochemical activation of vinyl azides and demonstrated wide substrate scope. In the photochemical reaction, blue light (456 nm) alone triggered photolysis of the azide without the addition of a photocatalyst. Possible reaction mechanisms in the context of substrate reactivity are discussed.
RESUMEN
A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700 µM), and high oral bioavailability in rats (83%).
RESUMEN
Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic beta-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.
Asunto(s)
Glucemia/metabolismo , Resina de Colestiramina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Péptido 1 Similar al Glucagón/biosíntesis , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Animales , Glucemia/análisis , Resina de Colestiramina/farmacología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Expresión Génica , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/análisis , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Receptores X del Hígado , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/fisiología , Péptido YY/metabolismo , Ratas , Ratas Zucker , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/fisiologíaRESUMEN
A series of benzisothiazole- and indolizine-ß-d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure-activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC50 of 10 nM.
RESUMEN
The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Pirimidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Tiofenos/síntesis química , Administración Oral , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/fisiología , Genes Reporteros , Semivida , Humanos , Ratones , Ratones Obesos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaAsunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Obesidad/tratamiento farmacológico , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/uso terapéutico , Modelos Animales de Enfermedad , Metabolismo Energético , Humanos , Hormonas Hipotalámicas/fisiología , Leptina/fisiología , Melaninas/fisiología , Obesidad/metabolismo , Hormonas Hipofisarias/fisiologíaRESUMEN
Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.