RESUMEN
A series of potent carboxylic acid DGAT1 inhibitors with high permeability were developed from a virtual screening hit. Strategies were employed to reduce Pgp substrate recognition and increase passive permeability, resulting in the discovery of a series showing good inhibition of cellular triglyceride synthesis. The mutagenic potential of prospective metabolites was evaluated in the Ames assay, and one aniline was shown to be devoid of mutagenicity.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Células CACO-2 , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Permeabilidad/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.
Asunto(s)
Glucoquinasa/metabolismo , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Sulfonas/química , Sulfonas/farmacología , Tiazoles/química , Tiazoles/farmacología , Animales , Activación Enzimática , Femenino , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/enzimología , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Sulfonas/efectos adversos , Sulfonas/farmacocinética , Tiazoles/efectos adversos , Tiazoles/farmacocinéticaRESUMEN
The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
Asunto(s)
Depresores del Apetito/farmacología , Conducta Alimentaria/efectos de los fármacos , Ácidos Oléicos/metabolismo , Ácidos Oléicos/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Depresores del Apetito/administración & dosificación , Depresores del Apetito/química , AMP Cíclico/metabolismo , Dieta , Relación Dosis-Respuesta a Droga , Endocannabinoides , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Obesidad/tratamiento farmacológico , Ácidos Oléicos/administración & dosificación , Ácidos Oléicos/química , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Especificidad por Sustrato , Factores de Tiempo , Levaduras/metabolismoRESUMEN
The synthesis, SAR and biological evaluation of a series of ureas that activate glucokinase, a target for diabetes therapy as a result of its critical role in the regulation of whole-body glucose homeostasis, are described. Some of the urea-containing glucokinase activators lowered blood glucose levels in vivo following oral dosing to C57BL/6J mice.