The development and SAR of pyrrolidine carboxamide 11beta-HSD1 inhibitors.

The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.

Antisense inhibition of 11betahydroxysteroid dehydrogenase type 1 improves diabetes in a novel cortisone-induced diabetic KK mouse model.

The inhibition of 11betahydroxysteroid dehydrogenase 1 (11betaHSD1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is an attractive target to treat diabetes by suppressing hepatic gluconeogenesis. To test this hypothesis, we developed a novel glucocorticoid-induced diabetic KK mouse model and used 11betaHSD1 antisense oligonucleotide (ASO) as an inhibitory tool. KK mice were treated with 25 or 50mg/kg/day of 11betaHSD1 ASO for 28 days. On day 25, cortisone pellets were surgically implanted to induce diabetes. In the ASO-treated mice, plasma blood glucose levels were significantly reduced by up to 54%. In parallel, cortisol and other diabetes endpoints were also significantly reduced. Hepatic 11betaHSD1 mRNA was suppressed by up to 84% with a concomitant respective decrease of up to 49% in the expression of PEPCK. The results suggest that inhibition of 11betaHSD1 activity reduces the availability of cortisol to activate the glucocorticoid receptor, down regulates gluconeogenesis and thus reduces plasma glucose levels in cortisone-induced diabetic KK mice.

Demonstration of proof of mechanism and pharmacokinetics and pharmacodynamic relationship with 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), an inhibitor of 11 -hydroxysteroid dehydrogenase type 1, in cynomolgus monkeys.

Glucocorticoids, through activation of the glucocorticoid receptor (GR), regulate hepatic gluconeogenesis. Elevated hepatic expression and activity of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) play a key role in ligand-induced activation of the GR through the production of cortisol. Evidence from genetically modified mice suggests that inhibition of 11betaHSD1 might be a therapeutic approach to treat the metabolic syndrome. We have identified a potent 11betaHSD1 inhibitor, 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide (PF-915275), that is selective for the primate and human enzymes. The objective of this study was to demonstrate target inhibition with PF-915275 and to quantify the relationship between target inhibition and drug exposure in monkeys. We characterized the ability of PF-915275 to inhibit the conversion of prednisone, a synthetic cortisone analog that can be distinguished from the endogenous substrate cortisone, enabling a direct measure of substrate to product conversion without the complication of feedback. Adult cynomolgus monkeys were administered either vehicle or various doses of PF-915275 followed by a 10-mg/kg dose of prednisone. Prednisone conversion to prednisolone and the concentrations of PF-915275 were measured by liquid chromatography/tandem mass spectrometry. PF-915275 dose-dependently inhibited 11betaHSD1-mediated conversion of prednisone to prednisolone, with a maximum of 87% inhibition at a 3-mg/kg dose. An exposure-response relationship was demonstrated, with an estimated EC(50) of 391 nM (total) and 17 nM (free). Insulin levels were also reduced in a dose-related manner. These results should enable the development of a biomarker for evaluating target modulation in humans that will aid in identifying 11betaHSD1 inhibitors to treat diabetes and other related metabolic diseases.

LPS-induced biomarkers in mice: a potential model for identifying insulin sensitizers.

The contribution of nutrient overload and associated inflammation to insulin resistance has highlighted several therapeutic targets including c-Jun N-terminal kinase (JNK) and S6 kinase (S6K). To investigate how a lipopolysaccharide (LPS)-mediated inflammatory response may modulate pathways implicated in insulin resistance, we characterized the LPS-induced changes in key biomarkers. Administration of 0.06-4 mg/kg LPS to C57BL/6 mice stimulated increases in plasma levels of TNFalpha, IL-12p40, IL-6 and MCP-1 and in JNK activity as measured by phosphorylated c-Jun in fat. For the first time, we show that LPS induces S6K activity by up to 6.1-fold, as measured by the phosphorylation of S6 ribosomal protein in liver, and increases by up to 1.8-fold, plasma levels of the novel pro-inflammatory cytokine osteopontin which is implicated in the pathogenesis of insulin resistance. These novel findings suggest that LPS administration may form the basis of an acute in vivo pharmacodynamic model for therapies targeting multiple pathways implicated in insulin resistance.

Características clínicas y epidemiológicas en pacientes pediátricos del Instituto Especializado de Salud del Niño (IESN) 2006-2009, Diagnósticados por anatomopatología con helicobacter positivo / Clinical and epidemiological characteristics in pediatric patients at the Institute of Child Health Specialist(INSN)2006-2009, diagnosed by pathology with positive helicpbacter

Introducción; La- infección por Helicobacter Pylori ampliamente difundida en todo el mundo, y es considerada como una de las principales causas de gastritis crónica, ulceras duodenales, pépticas y cáncer gástrico. Actualmente, en nuestro país la prevalencia de la infección por Helicobacter pylori en niños es desconocida. Objetivos: En nuestro estudio tenemos como objetivo principal identificar las características clínicas y epidemiológicas más frecuentes en pacientes con biopsia positiva para Helicobacter pylori. Materiales y Método: Este estudio es descriptivo y analítico. La población de estudio son las biopsias positivas a Helicobacter pylori de pacientes pediátricos de 0 a 17 años, tanto hospitalizados como los que acudieron a Consultorio Externo, registradas desde Julio 2006 a Julio 2009 en eI IESN, procedentes de todo el Perú. La muestra está dada según los criterios de inclusión y exclusión Resultados: Er síntoma de dolor abdominal obtuvo un porcentaje de 29.14 por ciento, fue el más frecuente en nuestra población de estudio. Conclusiones: Se concluye por lo tanto que la población infantil estudiada, presenta como síntoma principal asociado a la infección por Helicobacter pylori al dolor abdominal

Introduction; Helicobacter pylori infection (Hp) is widely spread around the world, and it is considered one of the main causes of chronic gastritis, peptic and duodenal ulcers, and gastric cancer Actually, in our country the prevalence of Helicobacter pylori's infection in pediatric's 'population is unknown. Objectives: In our study, our main objective is to identify clinical and epidemiological most frequent characteristics of Helicobacter pylori's infection in pediatricÆs population. Materials and Methods: This is a descriptive and analytic study. Our population of study is the pediatric population between 0 and 17 diagnosed with posítive biopsies tor Heucobacter Pylori; hospitalized and ambulatory between July 2006 and July 2009 in the IESN. Results: Abdominal pain had a percentage of 29.14 por ciento, was the most frequent symptom in our study. Conclusions: we conclude that our pediatric population In study, presents abdominal pain as main symptom associated to Helicobacter Pylori. 's infection