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1.
Bioorg Med Chem ; 49: 116424, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34626901

RESUMEN

Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD). We investigated the relationship between in silico physicochemical properties and hERG and PLD, and explored well-balanced agonists to identify amide 19 and benzimidazole 30. As a result of this exploration, we found out that the value of (cLogP) [2] + (pKa) [2] needs to be less than 110 to mitigate the liabilities.


Asunto(s)
Amidas/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Fosfolípidos/antagonistas & inhibidores , Receptores de Somatostatina/agonistas , Amidas/síntesis química , Amidas/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Estructura Molecular , Fosfolípidos/metabolismo , Relación Estructura-Actividad
2.
Nat Med ; 10(11): 1208-15, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15489860

RESUMEN

Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.


Asunto(s)
Tejido Adiposo/metabolismo , Regulación de la Expresión Génica , Insulina/metabolismo , Obesidad/prevención & control , Monoéster Fosfórico Hidrolasas/metabolismo , Transducción de Señal/fisiología , Termogénesis/fisiología , Proteínas Supresoras de Tumor/metabolismo , Adiponectina , Animales , Peso Corporal , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Cartilla de ADN , Metabolismo Energético/fisiología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Mitocondrias/metabolismo , Fosfohidrolasa PTEN , Fosfatidilinositoles/metabolismo , Regiones Promotoras Genéticas/genética , Factores de Transcripción/metabolismo
3.
ACS Chem Neurosci ; 11(10): 1482-1494, 2020 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-32315148

RESUMEN

Acromegaly is a disease caused by the oversecretion of growth hormone. It is currently treated by intravenous injection with cyclic peptide drugs that activate somatostatin receptor subtype 2 (SSTR2). Here, novel nonpeptidic, small-molecule, and orally active SSTR2 agonists were identified from a hit compound (13). Pharmacophore studies enabled scaffold hopping to obtain a unique 3,4,5-trisubstituted pyridine motif. Further optimization conferred potent SSTR2 agonistic activity and metabolic stability. Several compounds were evaluated and these showed good oral pharmacokinetic profiles in rats, and one representative compound (25) showed highly potent inhibition of growth hormone secretion induced by growth hormone-releasing hormone in rats. Based on these results, 25 was identified as a promising lead for further optimization. A structure-activity relationship (SAR) study and the metabolic stability data for this compound are also described.


Asunto(s)
Acromegalia , Acromegalia/tratamiento farmacológico , Animales , Hormona del Crecimiento , Ratas , Receptores de Somatostatina/agonistas , Somatostatina , Relación Estructura-Actividad
4.
J Clin Invest ; 114(12): 1752-61, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15599400

RESUMEN

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.


Asunto(s)
Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Estrés Oxidativo , Células 3T3-L1 , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Anciano , Animales , Antioxidantes/química , Antioxidantes/metabolismo , Peso Corporal , Diferenciación Celular , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/metabolismo , Immunoblotting/métodos , Peroxidación de Lípido , Masculino , Síndrome Metabólico/patología , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Persona de Mediana Edad , Modelos Biológicos , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Obesidad/patología , Oxidación-Reducción , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de Tiempo
5.
Diabetes ; 52(7): 1655-63, 2003 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12829629

RESUMEN

Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-gamma/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-gamma-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-gamma and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular , Proteínas/genética , Receptores Citoplasmáticos y Nucleares/fisiología , Receptores de Ácido Retinoico/fisiología , Factores de Transcripción/fisiología , Células 3T3 , Adiponectina , Animales , Secuencia de Bases , Línea Celular , Cartilla de ADN , ADN Complementario/genética , Genes Reporteros , Humanos , Hipoglucemiantes , Luciferasas/genética , Ratones , Regiones Promotoras Genéticas , Receptores X Retinoide , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección
6.
J Biol Chem ; 280(25): 23653-9, 2005 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-15764598

RESUMEN

Sulfonylurea (SU) agents, including glimepiride and glibenclamide, are the most widely used oral hypoglycemic drugs, which stimulate insulin secretion primarily by binding to the SU receptor on the plasma membrane of pancreatic beta-cells. Thiazolidinediones, such as pioglitazone and rosiglitazone, are other hypoglycemic agents that effectively improve peripheral insulin resistance through activation of peroxisome proliferator-activated receptor gamma (PPARgamma). In the present study, we found that glimepiride specifically induced the transcriptional activity of PPARgamma in luciferase reporter assays. Glimepiride enhanced the recruitment of coactivator DRIP205 and dissociation of corepressors such as nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors. In addition, glimepride directly bound to PPARgamma in a manner competitive to rosiglitazone, which is a proven ligand for PPARgamma. Furthermore, in 3T3-L1 adipocytes, glimepiride stimulated the transcriptional activity of the gene promoter containing PPAR-responsive element and altered mRNA levels of PPARgamma target genes including aP2, leptin, and adiponectin. Finally, glimepiride induced adipose differentiation in 3T3-F442A cells, which was known to differentiate into adipocytes in a PPARgamma-dependent manner. Most effects observed with glimepiride were also seen with glibenclamide. These data strongly suggest that glimepiride and glibenclamide, both of which belong to SU agents, should have PPARgamma agonist activity, whose potencies were 16-25% of the maximum level achieved by pioglitazone. Our observation that glimepiride and glibenclamide could act not only on SU receptor but also on PPARgamma may give an important clue to the development of novel antidiabetic drugs, which can enhance both insulin secretion from pancreatic beta-cells and peripheral insulin sensitivity.


Asunto(s)
Gliburida/farmacología , PPAR gamma/agonistas , Compuestos de Sulfonilurea/farmacología , Células 3T3-L1 , Animales , Secuencia de Bases , Línea Celular , Cartilla de ADN , Humanos , Ratones
7.
Biochem Biophys Res Commun ; 331(2): 520-6, 2005 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-15850790

RESUMEN

Adiponectin, an adipose-derived hormone, exhibits various biological functions, such as increasing insulin sensitivity, protecting hypertension, and suppression of atherosclerosis, liver fibrosis, and tumor growth. Here, we report the role of adiponectin on bone metabolism. C57BL/6J mice were treated with adenovirus expressing lacZ or adiponectin, and their bones were analyzed by three-dimensional microcomputed tomography. Adiponectin-adenovirus treatment increased trabecular bone mass, accompanied by decreased number of osteoclasts and levels of plasma NTx, a bone-resorption marker. In vitro studies showed that adiponectin inhibited M-CSF- and RANKL-induced differentiation of mouse bone marrow macrophages and human CD14-positive mononuclear cells into osteoclasts and also suppressed the bone-resorption activity of osteoclasts. Furthermore, adiponectin enhanced mRNA expression of alkaline phosphatase and mineralization activity of MC3T3-E1 osteoblasts. Our results indicate that adiponectin exerts an activity to increase bone mass by suppressing osteoclastogenesis and by activating osteoblastogenesis, suggesting that adiponectin manipulation could be therapeutically beneficial for patients with osteopenia.


Asunto(s)
Desarrollo Óseo , Huesos/citología , Huesos/metabolismo , Diferenciación Celular , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Osteoclastos/metabolismo , Adenoviridae/genética , Adiponectina , Animales , Células Cultivadas , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Tamaño de los Órganos , Osteoblastos/citología , Osteoblastos/metabolismo , Osteoclastos/citología
8.
J Biol Chem ; 279(41): 42867-74, 2004 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-15292182

RESUMEN

Intestinal epithelial cells undergo rapid turnover and exfoliation especially at the villus tips. This process is modulated by various nutrients especially fat. Apoptosis is one of the important regulatory mechanisms of this turnover. Therefore, identification of the factors that control epithelial cell apoptosis should help us understand the mechanism of intestinal mucosal turnover. Here, we report the identification of a novel small intestine-specific member of the Ly-6 family, intectin, by signal sequence trap method. Intectin mRNA expression was exclusively identified in the intestine and localized at the villus tips of intestinal mucosa, which is known to undergo apoptosis. Intectin mRNA expression was modulated by nutrition. Intestinal epithelial cells expressing intectin were more sensitive to palmitate-induced apoptosis, compared with control intestinal epithelial cells, and such effect was accompanied by increased activity of caspase-3. Intectin expression also reduced cell-cell adhesion of intestinal epithelial cells.


Asunto(s)
Apoptosis , Células Epiteliales/metabolismo , Glicosilfosfatidilinositoles/química , Mucosa Intestinal/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Northern Blotting , Western Blotting , Caspasa 3 , Caspasas/metabolismo , Membrana Celular/metabolismo , Clonación Molecular , Citosol/metabolismo , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Epitelio/metabolismo , Vectores Genéticos , Hibridación in Situ , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Ácido Palmítico/química , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Fracciones Subcelulares , Factores de Tiempo , Distribución Tisular
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