RESUMEN
A series of novel spirocyclic DGAT1 inhibitors containing the oxadiazole motif were designed and synthesized for biological evaluation. Several compounds exhibited potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activity. Optimization of the series led to the identification of five lead compounds 8, 9, 10, 11 and 12 that showed excellent in-vitro activity with IC50 values ranging from 7 to 20 nM against human DGAT1. All compounds demonstrated good druggability as well as microsomal stability and safety profiles such as hERG and CYP. Compound 12 significantly reduced plasma triglyceride levels in-vivo in the mouse model of acute lipid challenge. Significant reduction in plasma TG excursion was observed, thus indicating DGAT1 inhibition in-vivo.
Asunto(s)
Ácidos Carboxílicos , Diacilglicerol O-Acetiltransferasa , Inhibidores Enzimáticos , Animales , Ácidos Carboxílicos/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Modelos Animales de Enfermedad , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Ratones , Oxadiazoles/farmacología , TriglicéridosRESUMEN
The activation of Nod-like receptor proteins (NLRP3) containing the pyrin domain inflammasome is a hallmark of the pathogenesis of metabolic disorders. Inhibition of the NLRP3 inflammasome by phytoconstituents has been attempted as a strategy to mitigate these disorders. Therefore, the present study aimed to evaluate the efficacy of an NLRP3 inflammasome inhibitor, parthenolide (PN; 5 mg/kg i.p.) against inflammation and insulin resistance in high-fat diet (HFD) - obese mice. Treatment with PN and pioglitazone (PIO; 30 mg/kg p.o.) attenuated lipopolysaccharide (LPS; 1 ng/ml) - induced elevation of tumor necrosis factor-α and interleukin-1ß in mouse peritoneal macrophages in a dose-dependent manner. Sixty days of PN and PIO treatment marginally reduced obesity-induced insulin resistance in HFD-obese mice. PN treatment also decreased blood glucose from 14th to 60th day, supporting the hypothesis of simultaneous attenuation of inflammation and insulin resistance in obese mice. Thus, PN treatment was also evident with significant improvement in glucose tolerance and peripheral insulin resistance validated through the respective tolerance tests. Therefore, the present study suggests that PN, an NLRP3 inflammasome inhibitor, could be a possible therapeutic agent for attenuating obesity-induced insulin resistance.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Sesquiterpenos/farmacología , Animales , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Interleucina-1beta/metabolismo , Macrófagos Peritoneales/metabolismo , Masculino , Ratones Endogámicos C57BL , Obesidad/etiología , Pioglitazona/farmacología , Pioglitazona/uso terapéutico , Sesquiterpenos/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: Irisin is known to be an important metabolic regulator of glucose and lipid metabolism. The aims of the present study are to assess the role of mouse Irisin in obesity and energy metabolism and its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) mice model. METHODS: DIO mice were treated with recombinant murine Irisin or vehicle, and parameters such as body weight, feed intake, glucose, and lipid levels, obesity, energy consumption, and insulin sensitivity were assessed. mRNA and protein levels of UCP1 and different thermogenesis biomarker were evaluated by quantitative real-time PCR and Western blot, respectively, in tissues and major metabolic organs. RESULTS: Irisin decreased body weight and whole-body fat mass in DIO mice in a dose dependent manner due to marked increases in total energy expenditure. It also lowered blood glucose, insulin, and lipid levels and possibly reversed hepatic steatosis. Irisin improved hepatic and peripheral insulin sensitivity in DIO mice along with body weight reduction and adiposity. Gene expression of UCP1 in different organs (adipose tissue and major organs, i.e., liver, kidney, heart, brain, and spleen) have suggested the role of irisin is global. Gene expression profile of different biomarkers in spleen suggest a profound role of Irisin in inflammation. Liver tissue have also shown significant increase of UCP1 expression in dose dependent manner which suggest a role of irisin in liver.
Asunto(s)
Dieta Alta en Grasa , Metabolismo Energético , Fibronectinas/metabolismo , Termogénesis , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Proteínas Recombinantes/metabolismo , Pérdida de PesoRESUMEN
New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.
Asunto(s)
Hipoglucemiantes , PPAR alfa , PPAR gamma , Animales , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Ratones , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Humanos , Relación Estructura-Actividad , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Estructura Molecular , Relación Dosis-Respuesta a Droga , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Simulación del Acoplamiento Molecular , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
A new series of analogues or derivatives of the previously reported PPARα/γ dual agonist LT175 allowed the identification of ligand 10, which was able to potently activate both PPARα and -γ subtypes as full and partial agonists, respectively. Docking studies were performed to provide a molecular explanation for this different behavior on the two different targets. In vivo experiments showed that this compound induced a significant reduction in blood glucose and lipid levels in an STZ-induced diabetic mouse model displaying no toxic effects on bone, kidney, and liver. By examining in depth the antihyperglycemic activity of 10, we found out that it produced a slight but significant inhibition of the mitochondrial pyruvate carrier, acting also through insulin-independent mechanisms. This is the first example of a PPARα/γ dual agonist reported to show this inhibitory effect representing, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , PPAR alfa , Ratones , Animales , PPAR alfa/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Transportadores de Ácidos Monocarboxílicos , Agonistas de PPAR-gamma , PPAR gamma/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéuticoRESUMEN
GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 µM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.
Asunto(s)
Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Administración Oral , Animales , Concentración 50 Inhibidora , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.