RESUMEN
(2S,3R,4R,5S,6R)-2-Aryl-5,5-difluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols and (2S,3R,4R,5S,6R)-2-aryl-5-fluoro-5-methyl-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols were discovered as dual inhibitors of sodium glucose co-transporter proteins (e.g. SGLT1 and SGLT2) through rational drug design, efficient synthesis, and in vitro and in vivo evaluation. Compound 6g demonstrated potent dual inhibitory activities (IC50 = 96 nM for SGLT1 and IC50 = 1.3 nM for SGLT2). It showed robust inhibition of blood glucose excursion in an oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats when dosed at both 1 mg/kg and 10 mg/kg orally. It also demonstrated postprandial glucose control in db/db mice when dosed orally at 10 mg/kg.
Asunto(s)
Glucósidos/química , Hipoglucemiantes/química , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Transportador 2 de Sodio-Glucosa/química , Transportador 2 de Sodio-Glucosa/metabolismo , Animales , Glucemia/análisis , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/patología , Modelos Animales de Enfermedad , Diseño de Fármacos , Prueba de Tolerancia a la Glucosa , Glucósidos/metabolismo , Glucósidos/farmacología , Glucósidos/uso terapéutico , Semivida , Halogenación , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Ratas , Ratas Sprague-Dawley , Transportador 1 de Sodio-Glucosa/metabolismo , Relación Estructura-ActividadRESUMEN
G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of ß-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.
Asunto(s)
Quinasa 2 del Receptor Acoplado a Proteína-G/antagonistas & inhibidores , Ftalazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Animales , Pruebas de Enzimas , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Células HEK293 , Humanos , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Miocitos Cardíacos/efectos de los fármacos , Ftalazinas/síntesis química , Ftalazinas/farmacocinética , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/síntesis química , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Relación Estructura-ActividadRESUMEN
A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50â¯=â¯43â¯nM for SGLT1 and IC50â¯=â¯9â¯nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10â¯mg/kg.
Asunto(s)
Desoxiglucosa/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Administración Oral , Animales , Glucemia/efectos de los fármacos , Desoxiglucosa/administración & dosificación , Desoxiglucosa/análogos & derivados , Desoxiglucosa/síntesis química , Diseño de Fármacos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Macaca fascicularis , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas Sprague-Dawley , Ratas Zucker , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/síntesis química , Inhibidores del Cotransportador de Sodio-Glucosa 2/química , Relación Estructura-ActividadRESUMEN
The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and ß-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated ß-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.