RESUMEN
Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.
Asunto(s)
Pirazoles , Pirimidinas , Animales , Perros , Canal de Potasio ERG1/metabolismo , Canales de Potasio Éter-A-Go-Go , Éteres , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.
Asunto(s)
Antineoplásicos/farmacología , Pirimidinas/farmacología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación de Dinámica Molecular , Estructura Molecular , Células 3T3 NIH , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Pirimidinas/administración & dosificación , Pirimidinas/química , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Solubilidad , Relación Estructura-Actividad , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Renal inflammation is a final common pathway of chronic kidney disease (CKD), and its progression can be used to effectively gauge the degree of renal dysfunction. Inflammatory mechanisms contribute to glomerulosclerosis and tubulointerstitial fibrosis, which are hallmarks of CKD leading to end-stage renal disease. Receptor-interacting protein kinase 2 (RIP2) is largely committed to nucleotide-binding oligomerization domain signaling as a direct effector and transmits nuclear factor-κB (NF-κB)-mediated proinflammatory cytokine production. In the present study, we hypothesized that if inflammation via RIP2 and NF-κB signaling plays an important role in renal failure, then the anti-inflammatory effect of RIP2 inhibitors should be effective in improving CKD. To determine its pharmacologic potency, we investigated the renoprotective properties of the novel RIP2 inhibitor AS3334034 [7-methoxy-6-(2-methylpropane-2-sulfonyl)-N-(4-methyl-1H-pyrazol-3-yl)quinolin-4-amine] in uninephrectomized adriamycin-induced CKD rats. Six weeks' repeated administration of AS3334034 (10 mg/kg, once daily) significantly reduced urinary protein excretion and prevented the development of glomerulosclerosis and tubulointerstitial fibrosis. In addition, AS3334034 showed beneficial effects on renal function, as demonstrated by a decrease in levels of plasma creatinine and blood urea nitrogen and attenuation of a decline in creatinine clearance. Furthermore, AS3334034 significantly attenuated inflammation, renal apoptosis, and glomerular podocyte loss. These results suggest that the RIP2 inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect and is therefore potentially useful in treating patients with CKD. SIGNIFICANCE STATEMENT: The receptor-interacting protein kinase 2 (RIP2) inhibitor AS3334034 suppresses the progression of chronic renal failure via an anti-inflammatory effect, suggesting that the nucleotide-binding oligomerization domain-RIP2 axis might play a crucial role in the pathogenesis of inflammatory kidney diseases. AS3334034 is expected to be potentially useful in the treatment of patients with chronic kidney disease.
Asunto(s)
Doxorrubicina/farmacología , Riñón/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/antagonistas & inhibidores , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/metabolismo , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Progresión de la Enfermedad , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Riñón/metabolismo , Pruebas de Función Renal/métodos , Masculino , FN-kappa B/metabolismo , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Relación Estructura-Actividad , Triazinas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4-ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4-ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4-ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure-activity relationship (SAR) using computational modeling.
Asunto(s)
Amidas/química , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/síntesis química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Pirazinas/química , Células 3T3 , Amidas/metabolismo , Amidas/farmacología , Amidas/uso terapéutico , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Humanos , Ratones , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Solubilidad , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/química , Glucósidos/uso terapéutico , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Azulenos/química , Azulenos/uso terapéutico , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Transportador 2 de Sodio-Glucosa/metabolismoRESUMEN
BACKGROUND AND AIM: Sodium-glucose cotransporter (SGLT) 2 is a specifically expressed transporter in the kidney that plays an important role in renal glucose reabsorption, and its inhibition may present a novel therapeutic strategy for treating diabetes. Here, we pharmacologically characterized YM543, a newly synthesized SGLT2 selective inhibitor to test this theory. RESULTS: In vitro studies revealed that YM543 potently and selectively inhibited mouse and human SGLT2 activities at nanomolar ranges. In vivo single oral administration of YM543 dose-dependently and significantly reduced blood glucose levels and improved glucose tolerance with a concomitant increase in urinary glucose excretion in KK/Ay type 2 diabetic mice, effects that were sustained even after 12 h. Repeated once-daily oral administration of YM543 for 5 weeks significantly reduced hyperglycemia in type 2 diabetic mice. In addition, combination treatment of YM543 with rosiglitazone or metformin additively improved diabetic symptoms. In contrast, YM543 did not affect normoglycemia at pharmacological doses in normal mice. CONCLUSIONS: Results from the present study suggest that YM543 is an orally active SGLT2 selective inhibitor which reduces hyperglycemia with a concomitant increase in urinary glucose excretion, indicating its promise as an effective treatment against type 2 diabetes.
RESUMEN
A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.
Asunto(s)
Glucemia/efectos de los fármacos , Glucósidos/química , Glucósidos/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/química , Tiofenos/farmacología , Animales , Células CHO , Cricetinae , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glucósidos/síntesis química , Glucósidos/farmacocinética , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Concentración 50 Inhibidora , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Tiofenos/síntesis química , Tiofenos/farmacocinéticaRESUMEN
Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption, and inhibition of renal SGLT2 activity represents an innovative strategy for the treatment of hyperglycemia in diabetic patients. The present study investigated the antidiabetic effects of ipragliflozin, a SGLT2-selective inhibitor, in streptozotocin-nicotinamide-induced mildly diabetic mice, which exhibited a mild decline in glucose tolerance associated with the loss of early-phase insulin secretion. Oral administration of ipragliflozin increased urinary glucose excretion in a dose-dependent manner, an effect which was significant at doses of 0.3 mg/kg or higher and lasted over 12 h. In addition, ipragliflozin dose-dependently improved hyperglycemia and glucose intolerance with concomitant decreases in plasma insulin levels without causing hypoglycemia. Once-daily dosing of ipragliflozin (0.1 - 3 mg/kg) for 4 weeks attenuated hyperglycemia, glucose intolerance, and impaired insulin secretion. These results suggest that the SGLT2-selective inhibitor ipragliflozin increases urinary glucose excretion by inhibiting renal glucose reabsorption, improves hyperglycemia in streptozotocin-nicotinamide-induced mildly diabetic mice, and may be useful for treating type 2 diabetes.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Glucósidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/uso terapéutico , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Glucósidos/farmacología , Hipoglucemiantes/farmacología , Insulina/sangre , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Niacinamida , Transportador 2 de Sodio-Glucosa , Estreptozocina , Tiofenos/farmacologíaRESUMEN
AIMS: The sodium-glucose cotransporter (SGLT) 2 inhibitor, ipragliflozin, improves not only hyperglycemia but also obesity in type 2 diabetic animals and patients; however, there have been concerns that it may also cause an increase in compensatory food intake. Appetite is regulated by complex mechanisms involving the central nervous system, part of which involves appetite-related hormones and arteriovenous differences in postprandial glucose levels. We evaluated the effect of ipragliflozin in type 2 diabetic rats on food intake, appetite-related hormones and arteriovenous differences in postprandial glucose levels, and their correlation with food intake. MAIN METHODS: Ipragliflozin and several antidiabetic drugs were administered to type 2 diabetic rats and various parameters concerning food intake were measured. KEY FINDINGS: Ipragliflozin significantly increased urinary glucose excretion and reduced postprandial hyperglycemia. Compared to normal rats, diabetic rats exhibited hyperphagia and elevated plasma levels of the appetite-stimulating hormones neuropeptide Y and ghrelin. Ipragliflozin induced significant weight loss and reduced plasma levels of appetite-stimulating hormones without affecting food intake. Diabetic rats exhibited a significantly reduced arteriovenous difference in postprandial glucose levels due to insulin insufficiency; this was improved by ipragliflozin, which increased renal arteriovenous differences in glucose levels by increasing urinary glucose excretion. SIGNIFICANCE: These results indicate that the SGLT2 inhibitor, ipragliflozin, exerts antihyperglycemic actions by increasing urinary glucose excretion, and induces weight loss without a compensatory increase in food intake in type 2 diabetic mice. The mechanisms underlying these effects can be attributed, in part, to an increased arteriovenous difference in postprandial glucose levels and improved regulation of appetite-related hormones in the diabetic animal model. While this study was conducted in rodents and the results may be distinct from those in humans, it is possible that some of the pharmacological mechanisms, including the regulation of appetite-related hormones, can be extrapolated to clinical settings and may be valuable for further studies including clinical investigations.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/metabolismo , Glucósidos/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/administración & dosificación , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/fisiología , Hipoglucemiantes/administración & dosificación , Masculino , Periodo Posprandial/efectos de los fármacos , Ratas , Ratas Wistar , Transportador 2 de Sodio-Glucosa , Resultado del TratamientoRESUMEN
Sivelestat sodium hydrate (ELASPOL) was effective for ARDS in a fifty-year-old female patient suffering from chronic rheumatoid arthritis with acute exacerbation, after failing to respond to high dose steroid pulse therapy. In ICU, the patient had bilateral lung opacities, especially of the upper lobes, respiratory acidosis, hypercapnea (PaCO2 89 mmHg), and poor oxygenation (P/F ratio 193). High dose steroid pulse therapy had been performed, but oxygenation was not improved, and a low level of oxygenation (P/F ratio 155) persisted. Sivelestat was started two days after finishing the steroid pulse therapy. The butterfly shadow on chest X ray and impaired oxygenation were markedly improved from the third day of sivelestat administration. Respiratory support was terminated with P/F ratio 300. Plasma concentrations of SP-A and SP-D decreased after sivelestat administration, but concentration of KL-6 was still elevated. In this case, sivelestat was effective for ARDS in the patient not responding to steroid pulse therapy, and clinical finding and plasma concentrations of SP-A and SP-D were correlated well.
Asunto(s)
Artritis Reumatoide/complicaciones , Glicina/análogos & derivados , Glicina/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Inhibidores de Serina Proteinasa/uso terapéutico , Sulfonamidas/uso terapéutico , Antígenos/sangre , Antígenos de Neoplasias , Biomarcadores/sangre , Femenino , Glicoproteínas/sangre , Humanos , Elastasa de Leucocito/antagonistas & inhibidores , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Mucina-1 , Mucinas , Proteína A Asociada a Surfactante Pulmonar/sangre , Proteína D Asociada a Surfactante Pulmonar/sangre , Quimioterapia por Pulso , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/etiología , Resultado del TratamientoRESUMEN
A 7-year-old girl suffered from withdrawal syndrome with systemic convulsion after sedation with midazolam and fentanyl. She had a history of severe accidental alkaline esophagitis, and under went polysurgeries. This time, she was scheduled to receive reconstruction of the esophagus with small intestine in order to resolve esophageal stenosis. Operation and anesthesia lasted for 14 hours, and 17 hours, respectively. In the postoperative period, she was under heavy sedation with midazolam and fentanyl in order to keep neck position immobile. Her sedation persisted for 14 postoperative days, and the total doses of midazolam and fentanyl were more than 100 mg x kg(-1), and 6.4 mg x kg(-1), respectively. Thereafter, her sedation was tapered and discontinued within about 24 hours. After 12 hours, she suddenly developed systemic convulsion with loss of consciousness. There was no evidence of obvious organic central nervous system abnormality. We suspected withdrawal syndrome, and gradual decrease of midazolam and fentanyl prevented her from going into withdrawal syndrome. We have to pay attention to withdrawal syndrome when heavy and long sedation with midazolam and fentanyl was employed and the drugs were then tapered and discontinued.
Asunto(s)
Fentanilo/efectos adversos , Hipnóticos y Sedantes/efectos adversos , Midazolam/efectos adversos , Convulsiones/inducido químicamente , Síndrome de Abstinencia a Sustancias , Niño , Enfermedad Crítica , Estenosis Esofágica/cirugía , Esofagoplastia , Femenino , Fentanilo/administración & dosificación , Humanos , Hipnóticos y Sedantes/administración & dosificación , Midazolam/administración & dosificación , Reoperación , Convulsiones/prevención & control , Factores de TiempoRESUMEN
Endotracheal tubes are known to have a risk of being displaced at neck extension or flexion or rotation. However, the displacement seldom causes clinical problems. An 74-year-old patient suffering from chronic rheumatoid arthritis underwent debridement in the infected knee under general anesthesia. Mechanical ventilation had to be continued because of poor oxygenation after the operation. She had been intubated with Hi Lo Evac endotracheal tube (HLE) for 3 days, then extubated. However, she again needed mechanical ventilation because of aggravated oxygenation. At that time, Profile cuff siliconised endotracheal tube (PCS) was placed for 3 days. We encountered dangerous displacement of HLE during the first mechanical ventilation, but did not have any clinically dangerous displacement of PCS during the second mechanical ventilation. Therefore, we compared the hardness of the three popular endotracheal tubes. We found the hardness of HLE was higher than the others. This might be one of the reasons for dangerous displacement of the endotracheal tube in our case.
Asunto(s)
Anestesia General , Artritis Reumatoide/cirugía , Desbridamiento , Intubación Intratraqueal/instrumentación , Respiración Artificial , Anciano , Artroplastia de Reemplazo de Rodilla , Femenino , Humanos , Intubación Intratraqueal/efectos adversosRESUMEN
OBJECTIVE: Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption and has been highlighted as a therapeutic target for the treatment of diabetes. Here, we investigated the therapeutic effects of SGLT2 selective inhibitor ipragliflozin in type 1 diabetic rats. METHODS: Type 1 diabetic rats were prepared by intravenous administration of streptozotocin (STZ). Ipragliflozin was acutely or chronically administered, and therapeutic effects were investigated. KEY FINDINGS: Single administration of ipragliflozin significantly increased urinary glucose excretion, and its effect lasted over 12 h. In addition, ipragliflozin improved glucose tolerance and sustainably reduced hyperglycaemia. Repeated administration of ipragliflozin to diabetic rats for 4 weeks significantly improved not only hyperglycaemia, but also hyperlipidaemia and hepatic steatosis with concomitant increases in urinary glucose excretion. In addition, ipragliflozin ameliorates renal glomerular hyperfiltration and albuminuria. Further, ipragliflozin reduced liver levels of oxidative stress biomarkers and plasma levels of inflammatory markers, and improved liver injury as assessed by plasma levels of aminotransferases. CONCLUSION: These results suggest that SGLT2 selective inhibitor ipragliflozin exerts a beneficial effect on glycaemic control and ameliorates diabetes-associated metabolic abnormalities and complications in STZ-induced diabetic rats, and would be a potential agent for the treatment of type 1 diabetes.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Hígado Graso/tratamiento farmacológico , Glucósidos/uso terapéutico , Hiperglucemia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/uso terapéutico , Albuminuria/tratamiento farmacológico , Albuminuria/etiología , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hígado Graso/etiología , Tasa de Filtración Glomerular/efectos de los fármacos , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/etiología , Glucósidos/farmacología , Hiperglucemia/etiología , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/etiología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Inflamación/etiología , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Estreptozocina , Tiofenos/farmacologíaRESUMEN
Ipragliflozin is a novel and selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption and thereby exerting a subsequent antihyperglycemic effect. Here, we examined the effect of ipragliflozin on body weight in high-fat diet-induced (HFD) obese rats. Treatment of ipragliflozin (10mg/kg once daily) reduced body weight despite a slight increase in food intake. Dual-energy X-ray absorptiometry and computed tomography demonstrated that the reduction in body weight was accompanied by reduced visceral and subcutaneous fat masses but not lean mass or bone mineral content. Analysis of plasma and urinary parameters suggested the possibility that ipragliflozin enhanced lipolysis and fatty acid oxidation, and indirect calorimetry showed that ipragliflozin decreased the heat production rate from glucose but increased the rate from fat and lowered the respiratory exchange ratio. In conclusion, these data demonstrate that ipragliflozin-induced urinary glucose excretion specifically reduces fat mass with steady calorie loss by promoting the use of fatty acids instead of glucose as an energy source in HFD rats. By improving hyperglycemia and promoting weight reduction, ipragliflozin may prove useful in treating type 2 diabetes in obese individuals.
Asunto(s)
Adiposidad/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Glucósidos/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Obesidad/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/farmacología , Animales , Biomarcadores/sangre , Biomarcadores/orina , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Glucosuria/metabolismo , Hipoglucemiantes/farmacología , Obesidad/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Oxidación-Reducción , Ratas , Transportador 2 de Sodio-Glucosa/metabolismo , Factores de Tiempo , Regulación hacia Arriba , Pérdida de Peso/efectos de los fármacosRESUMEN
The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance. Four-week repeated administration of ipragliflozin improved not only glucose tolerance, hyperglycemia, and hyperinsulinemia but also impaired insulin secretion, hyperlipidemia, hepatic steatosis, and obesity with a concomitant increase in urinary glucose excretion. In addition, ipragliflozin reduced plasma and liver levels of oxidative stress biomarkers (thiobarbituric acid reactive substances and protein carbonyl) and inflammatory markers (interleukin 6, tumor necrosis factor α, monocyte chemotactic protein-1, and c-reactive protein), and improved liver injury as assessed by plasma levels of aminotransferases. These results demonstrate that SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice and suggest that ipragliflozin may be useful in treating type 2 diabetes with metabolic syndrome.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Estrés Oxidativo/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/farmacología , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/orina , Dieta Alta en Grasa/efectos adversos , Hígado Graso/complicaciones , Hígado Graso/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Glucósidos/farmacocinética , Glucósidos/uso terapéutico , Glucosuria/tratamiento farmacológico , Hiperglucemia/complicaciones , Hiperglucemia/tratamiento farmacológico , Hiperlipidemias/complicaciones , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Insulina/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Masculino , Ratones , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Tiofenos/farmacocinética , Tiofenos/uso terapéuticoRESUMEN
The pharmacological profile of ipragliflozin (ASP1941; (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D: -glucitol compound with L: -proline (1:1)), a novel SGLT2 selective inhibitor, was investigated. In vitro, the potency of ipragliflozin to inhibit SGLT2 and SGLT1 and stability were assessed. In vivo, the pharmacokinetic and pharmacologic profiles of ipragliflozin were investigated in normal mice, streptozotocin-induced type 1 diabetic rats, and KK-A(y) type 2 diabetic mice. Ipragliflozin potently and selectively inhibited human, rat, and mouse SGLT2 at nanomolar ranges and exhibited stability against intestinal glucosidases. Ipragliflozin showed good pharmacokinetic properties following oral dosing, and dose-dependently increased urinary glucose excretion, which lasted for over 12 h in normal mice. Single administration of ipragliflozin resulted in dose-dependent and sustained antihyperglycemic effects in both diabetic models. In addition, once-daily ipragliflozin treatment over 4 weeks improved hyperglycemia with a concomitant increase in urinary glucose excretion in both diabetic models. In contrast, ipragliflozin at pharmacological doses did not affect normoglycemia, as was the case with glibenclamide, and did not influence intestinal glucose absorption and electrolyte balance. These results suggest that ipragliflozin is an orally active SGLT2 selective inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption, with subsequent antihyperglycemic effect and a low risk of hypoglycemia. Ipragliflozin has, therefore, the therapeutic potential to treat hyperglycemia in diabetes by increasing glucose excretion into urine.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Hipoglucemiantes/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Tiofenos/farmacología , Animales , Glucemia/análisis , Células CHO , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/orina , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/orina , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/orina , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Glucósidos/sangre , Glucósidos/farmacocinética , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Florizina/sangre , Florizina/farmacocinética , Ratas , Ratas Sprague-Dawley , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Tiofenos/sangre , Tiofenos/farmacocinéticaRESUMEN
PURPOSE: We investigated whether nitrous oxide can enhance the suppressive effect of propofol on spinal motor neuron excitability in humans. METHODS: Sixteen adult patients were prospectively randomly assigned to be given either propofol alone (group P; n = 8) or a supplement of 66% nitrous oxide with propofol (group PN; n = 8) for intraoperative sedation. Propofol was administered by a target-controlled infusion system to maintain sequentially increasing plasma propofol concentrations (Cpt) of 0.5, 0.8, 1.0, 1.3, 1.5 and 1.8 microg x ml(-1) in all patients. Assessment of the patient's level of sedation in both groups was performed with the Wilson Sedation Scale (WSS). F-wave analysis on the left abductor pollicis brevis muscle was carried out for the assessment of spinal motor neuron excitability at each plasma propofol concentration. RESULTS: Significant differences in the WSS scores between group P and group PN were observed at 0.8, 1.0, 1.3, and 1.5 microg x ml(-1) of Cpt (group P < group PN; P < 0.01). Cpt greater than 1.0 microg x ml(-1) significantly reduced F-wave persistence in a concentration-dependent manner, and the ICpt 50 and ICpt 95 values for plasma propofol concentration (plasma propofol concentrations that produced 50% and 95% inhibition of the baseline, respectively) were 1.05 and 1.95 microg x ml(-1) in group P, and 1.07 and 2.14 microg x ml(-1) in group PN, respectively. CONCLUSION: These results suggest that nitrous oxide can enhance the hypnotic effect, but not the suppression of spinal motoneuron excitability by propofol in humans at clinical levels of Cpt.
Asunto(s)
Anestésicos por Inhalación/farmacología , Anestésicos Intravenosos/farmacología , Hipnosis Anestésica/métodos , Neuronas Motoras/efectos de los fármacos , Óxido Nitroso/farmacología , Propofol/farmacología , Médula Espinal/efectos de los fármacos , Adulto , Análisis de Varianza , Anestésicos Intravenosos/sangre , Sedación Consciente/métodos , Sinergismo Farmacológico , Estimulación Eléctrica/métodos , Electrofisiología/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Propofol/sangre , Estudios ProspectivosRESUMEN
Effective preparation of cycloheptimidazol-4-ones was developed. The reactions of 2-tosyloxytropone (5) with amidines (6) carried out under simple conditions such as aq. NaOH in toluene at 35 degrees C afforded the corresponding cycloheptimidazol-4-ones (3) in low yield. However, by adding tetra-n-butylammonium bromide (n-Bu(4)NBr) to this reaction system, the yield was improved dramatically. The reaction conditions were screened in detail.