RESUMEN
Fructose consumption in humans and animals has been linked to enhanced de novo lipogenesis, dyslipidemia, and insulin resistance. Hereditary deficiency of ketohexokinase (KHK), the first enzymatic step in fructose metabolism, leads to essential fructosuria in humans, characterized by elevated levels of blood and urinary fructose following fructose ingestion but is otherwise clinically benign. To address whether KHK deficiency is associated with altered glucose and lipid metabolism, a Khk knockout (KO) mouse line was generated and characterized. NMR spectroscopic analysis of plasma following ingestion of [6-13C] fructose revealed striking differences in biomarkers of fructose metabolism. Significantly elevated urine and plasma 13C-fructose levels were observed in Khk KO vs. wild-type (WT) control mice, as was reduced conversion of 13C-fructose into plasma 13C-glucose and 13C-lactate. In addition, the observation of significant levels of fructose-6-phosphate in skeletal muscle tissue of Khk KO, but not WT, mice suggests a potential mechanism, whereby fructose is metabolized via muscle hexokinase in the absence of KHK. Khk KO mice on a standard chow diet displayed no metabolic abnormalities with respect to ambient glucose, glucose tolerance, body weight, food intake, and circulating trigylcerides, ß-hydroxybutyrate, and lactate. When placed on a high-fat and high-fructose (HF/HFruc) diet, Khk KO mice had markedly reduced liver weight, triglyceride levels, and insulin levels. Together, these results suggest that Khk KO mice may serve as a good model for essential fructosuria in humans and that inhibition of KHK offers the potential to protect from diet-induced hepatic steatosis and insulin resistance.
Asunto(s)
Dieta , Fructoquinasas/deficiencia , Errores Innatos del Metabolismo de la Fructosa/genética , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/genética , Dieta Alta en Grasa , Ingestión de Alimentos/genética , Fructoquinasas/genética , Fructoquinasas/metabolismo , Errores Innatos del Metabolismo de la Fructosa/metabolismo , Fructosafosfatos/sangre , Intolerancia a la Glucosa/genética , Resistencia a la Insulina , Metabolismo de los Lípidos/genética , Ratones NoqueadosRESUMEN
An active vanadium dioxide integrated metasurface offering broadband transmitted terahertz wave modulation with large modulation-depth under electrical control is demonstrated. The device consists of metal bias-lines arranged with grid-structure patterned vanadium dioxide (VO2) film on sapphire substrate. Amplitude transmission is continuously tuned from more than 78% to 28% or lower in the frequency range from 0.3 THz to 1.0 THz, by means of electrical bias at temperature of 68 °C. The physical mechanism underlying the device's electrical tunability is investigated and found to be attributed to the ohmic heating. The developed device possessing over 87% modulation depth with 0.7 THz frequency band is expected to have many potential applications in THz regime such as tunable THz attenuator.
RESUMEN
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
Asunto(s)
Antihipertensivos/farmacología , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Indazoles/farmacología , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/farmacocinética , Inhibidores de la Aromatasa/farmacología , Línea Celular , Cricetulus , Inhibidores del Citocromo P-450 CYP2D6/síntesis química , Inhibidores del Citocromo P-450 CYP2D6/farmacocinética , Inhibidores del Citocromo P-450 CYP2D6/farmacología , Humanos , Indazoles/síntesis química , Indazoles/farmacocinética , Macaca mulatta , Masculino , Ratas Sprague-Dawley , Estereoisomerismo , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidoresRESUMEN
Reported herein are a series of reverse indoles that represent novel non-steroidal mineralocorticoid receptor (MR) antagonists. The key structure-activity relationships (SAR) are presented below. This reverse indole series is exemplified by a compound that demonstrated efficacy in an acute natriuresis rodent model comparable to marketed MR antagonists, spironolactone and eplerenone.
Asunto(s)
Descubrimiento de Drogas , Indoles/farmacología , Antagonistas de Receptores de Mineralocorticoides/farmacología , Receptores de Mineralocorticoides/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Antagonistas de Receptores de Mineralocorticoides/síntesis química , Antagonistas de Receptores de Mineralocorticoides/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure-activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles.
Asunto(s)
Amidas/química , Compuestos Heterocíclicos/química , Antagonistas de Receptores de Mineralocorticoides/farmacología , Oxazoles/farmacología , Receptores de Mineralocorticoides/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Humanos , Microsomas Hepáticos , Antagonistas de Receptores de Mineralocorticoides/síntesis química , Antagonistas de Receptores de Mineralocorticoides/química , Estructura Molecular , Oxazoles/síntesis química , Oxazoles/química , Ratas , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To explore the safety in inguinal incarcerated hernia repair without use of antibiotics. METHODS: Retrospective statistical analysis was performed for a total 326 patients with inguinal incarcerated hernia repair at our hospital from January 2011 to July 2013. They were divided into 2 groups of non-using (n = 192) and using (n = 134) antibiotics. Statistical analysis of early postoperative infection was performed for two groups. RESULTS: The total incision infection had no statistical difference between two groups (7.29% (14/192) vs 3.73% (5/134), 0.52% (1/192) vs 1.49% (2/134), both P > 0.05). Further comparison of leukocyte count and neutrophil count at Day 3 showed no inter-group statistical difference ((7.9 ± 0.6) ×10(9) vs (7.8 ± 0.7) ×10(9)/L, (4.9 ± 0.5)×10(9) vs (5.0 ± 0.5) ×10(9)/L; U = 1.344, 1.777; P = 0.180, 0.077). CONCLUSION: It is unnecessary to use preventive antibiotics in patients undergoing tension-free repair with incarcerated inguinal hernia without high-risk infection or bowel necrosis.
Asunto(s)
Profilaxis Antibiótica , Hernia Inguinal/cirugía , Mallas Quirúrgicas , Adulto , Antibacterianos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure-activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics.
Asunto(s)
Antagonistas de Receptores de Mineralocorticoides/química , Oxazoles/química , Receptores de Mineralocorticoides/metabolismo , Animales , Sitios de Unión , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Microsomas/metabolismo , Antagonistas de Receptores de Mineralocorticoides/síntesis química , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Simulación del Acoplamiento Molecular , Oxazoles/síntesis química , Oxazoles/farmacocinética , Estructura Terciaria de Proteína , Ratas , Receptores de Mineralocorticoides/química , Relación Estructura-ActividadRESUMEN
Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationship (SAR) study was focused on improving the sEH inhibitory activity. Aminobenzisoxazoles emerged to be the optimal series, of which a potent human sEH inhibitor 7t was identified with a good pharmacokinetics (PK) profile. The strategy of employing aminoheterocycles as amide replacements may represent a general approach to develop mimics of known hydrolase or protease inhibitors containing an amide moiety.
Asunto(s)
Amidas/química , Compuestos de Anilina/química , Inhibidores Enzimáticos/química , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 Anillos/química , Isoxazoles/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Sitios de Unión , Simulación por Computador , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Epóxido Hidrolasas/metabolismo , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.
Asunto(s)
Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Hipertensión/tratamiento farmacológico , Piperidinas/química , Urea/análogos & derivados , Urea/farmacología , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/sangre , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Humanos , Modelos Moleculares , Unión Proteica , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Urea/uso terapéuticoRESUMEN
Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.
Asunto(s)
Aminas/química , Antihipertensivos/síntesis química , Inhibidores Enzimáticos/síntesis química , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos de Espiro/química , Urea/análogos & derivados , Animales , Antihipertensivos/química , Antihipertensivos/farmacocinética , Línea Celular , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Epóxido Hidrolasas/metabolismo , Humanos , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacocinéticaRESUMEN
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and weight loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. We describe the optimization of ß1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compounds proved essential in improving ß2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration.
RESUMEN
We propose and demonstrate a type of a broadband half-wave plate that operates in the reflective mode. It consists of a metal grating embedded in a dielectric slab and placed on top of a grounded metal surface. We theoretically show that owing to the optical feedback effect which originates from the wave reflections at the air-dielectric interface, the proposed half-wave plate exhibits a broadened and flattened response when comparing to the case where the feedback effect is absent. Such a prediction is validated using both numerical and experimental works carried out on a half-wave plate designed at 10 GHz. Moreover, our theoretical analysis also reveals that the half-wave plate has an interesting feature of broad angular response. Taking advantage of these features, we experimentally demonstrate that the proposed device can function as a freely tunable linear polarization converter with polarization conversion residues less than -20 dB in a wide frequency band, under the condition that the incident angle is as large as 45 degrees.
RESUMEN
Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.
RESUMEN
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Bencimidazoles/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Administración Oral , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Descubrimiento de Drogas , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , RatonesRESUMEN
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Cardiomegalia/inducido químicamente , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Imidazoles/farmacología , Piridinas/farmacología , Animales , Bencimidazoles , Glucemia/efectos de los fármacos , Ayuno , Glucógeno/metabolismo , Hipoglucemia/inducido químicamente , Imidazoles/efectos adversos , Imidazoles/química , Insulina/farmacología , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Piridinas/efectos adversos , Piridinas/químicaRESUMEN
We propose a kind of general framework for the design of a perfect linear polarization converter that works in the transmission mode. Using an intuitive picture that is based on the method of bi-directional polarization mode decomposition, it is shown that when the device under consideration simultaneously possesses two complementary symmetry planes, with one being equivalent to a perfect electric conducting surface and the other being equivalent to a perfect magnetic conducting surface, linear polarization conversion can occur with an efficiency of 100% in the absence of absorptive losses. The proposed framework is validated by two design examples that operate near 10 GHz, where the numerical, experimental and analytic results are in good agreements.
RESUMEN
Thiazolidinediones (TZDs), agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma), improve insulin sensitivity in vivo, and the mechanism remains largely unknown. In this study, we showed that, in Zucker obese (fa/fa) rats, acute (1-day) treatment with both rosiglitazone (a TZD) and a non-TZD PPARgamma agonist (nTZD) reduced plasma free fatty acid and insulin levels and, concomitantly, potentiated insulin-stimulated Akt phosphorylation at threonine 308 (Akt-pT308) in adipose and muscle tissues. A similar effect on Akt was observed in liver after a 7-day treatment. The increase in Akt-pT308 was correlated with an increase in Akt phosphorylation at serine 473 (Akt-pS473), tyrosine phosphorylation of insulin receptor beta subunit and insulin receptor substrate-1, and serine phosphorylation of glycogen synthase kinase-3alpha/beta. The agonists appeared to potentiate Akt1 phosphorylation in muscle and liver and both Akt1 and Akt2 in adipose. Finally, potentiation of insulin signaling was also observed in isolated adipose tissue ex vivo and differentiated 3T3 L1 adipocytes in vitro, but not in rat primary hepatocytes in vitro. These results suggest that 1) PPARgamma agonists acutely potentiate insulin signaling in adipose and muscle tissues and such regulation may be physiologically relevant to insulin sensitization in vivo; 2) the agonists directly target adipose tissues; and 3) the metabolic and signaling effects of the agonists are mediated by structurally distinct PPARgamma agonists.
Asunto(s)
Insulina/fisiología , Obesidad/fisiopatología , Receptores Citoplasmáticos y Nucleares/agonistas , Transducción de Señal/efectos de los fármacos , Tiazoles/farmacología , Tiazolidinedionas , Factores de Transcripción/agonistas , Tejido Adiposo/metabolismo , Animales , Ácidos Grasos no Esterificados/sangre , Femenino , Insulina/sangre , Proteínas Sustrato del Receptor de Insulina , Cinética , Hígado/enzimología , Músculo Esquelético/enzimología , Obesidad/genética , Fosfoproteínas/metabolismo , Fosforilación , Fosfoserina/metabolismo , Fosfotirosina/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Zucker , Receptor de Insulina/metabolismo , RosiglitazonaRESUMEN
Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.
Asunto(s)
Diabetes Mellitus Tipo 2/enzimología , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Complejos Multienzimáticos/metabolismo , Músculo Esquelético/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos no Esterificados/sangre , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Insulina/sangre , Cinética , Lípidos/sangre , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , PPAR alfa/agonistas , PPAR delta/agonistas , Fenilacetatos/síntesis química , Animales , Cricetinae , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Cinética , Masculino , Mesocricetus , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Modelos Moleculares , Estructura Molecular , Fenilacetatos/química , Fenilacetatos/farmacocinética , Fenilacetatos/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.