RESUMEN
We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section.
RESUMEN
We report the observation of 16 cosmic ray events with a mean energy of 1.5 × 10¹9 eV via radio pulses originating from the interaction of the cosmic ray air shower with the Antarctic geomagnetic field, a process known as geosynchrotron emission. We present measurements in the 300-900 MHz range, which are the first self-triggered, first ultrawide band, first far-field, and the highest energy sample of cosmic ray events collected with the radio technique. Their properties are inconsistent with current ground-based geosynchrotron models. The emission is 100% polarized in the plane perpendicular to the projected geomagnetic field. Fourteen events are seen to have a phase inversion due to reflection of the radio beam off the ice surface, and two additional events are seen directly from above the horizon. Based on a likelihood analysis, we estimate angular pointing precision of order 2° for the event arrival directions.
RESUMEN
Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/síntesis química , Piperazinas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adamantano/farmacocinética , Animales , Línea Celular , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Piperazinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.
Asunto(s)
Bencilaminas/síntesis química , Hipoglucemiantes/síntesis química , Receptores de Glucocorticoides/antagonistas & inhibidores , Sulfonamidas/síntesis química , Fosfatasa Alcalina/biosíntesis , Fosfatasa Alcalina/genética , Animales , Bencilaminas/efectos adversos , Bencilaminas/farmacología , Células Cultivadas , Cricetinae , Cricetulus , Dexametasona/farmacología , Femenino , Genes Reporteros , Glucocorticoides/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Ratones , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Embarazo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/genética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacología , Activación Transcripcional/efectos de los fármacos , Tirosina Transaminasa/biosíntesis , Útero/efectos de los fármacosRESUMEN
Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP. Gluconeogenesis, glycogenolysis, liver architecture, and hepatocyte composition are described to provide background information on hepatic function. Current methods of target validation for drug discovery, HGP measurement, diabetes animal models, as well as current drug therapies are covered. In the accompanying review article the new drug targets being probed to produce the next generation of therapies are described. Significant pharmaceutical and academic efforts to pharmacologically inhibit HGP has the opportunity to provide new therapeutics for type 2 diabetics.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/biosíntesis , Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Proteínas Portadoras/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Circulación Enterohepática/efectos de los fármacos , Humanos , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Factores de Transcripción/agonistas , Factores de Transcripción/antagonistas & inhibidoresRESUMEN
A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-beta-hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents. Several potential targets including glucose-6-phosphatase, glucose-6-phosphatase translocase, glycogen synthase kinase-3, adenosine receptor 2B antagonists, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase kinase, have been validated by compounds that are effective in animal models. Other targets like PGC-1a and CREB have initial validation support but no medicinal chemistry has been reported.
Asunto(s)
Glucosa/biosíntesis , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Depresión Química , HumanosRESUMEN
The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of the beta(2)-integrin family of adhesion molecules, and intracellular adhesion molecule ICAM-1 (cd54) is thought to play a critical role in the inflammatory process. On the basis of an anilino diaryl sulfide screening lead 1, in combination with pharmacophore analysis of other screening hits, we have identified an adjacent binding pocket. Subsequently, a p-ethenylcarbonyl linker was discovered to be optimal for accessing this binding site. Solution-phase parallel synthesis enabled rapid optimization of the cinnamides for this pocket. In conjunction with fine-tuning of the diaryl substituents, we discovered a novel series of potent, nonpeptide inhibitors of LFA-1/ICAM-1 interaction, exemplified by A-286982 (28h), which has IC(50) values of 44 and 35 nM in an LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assay, respectively.
Asunto(s)
Molécula 1 de Adhesión Intercelular/metabolismo , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Piperazinas/síntesis química , Sulfuros/síntesis química , Animales , Linfocitos B/citología , Linfocitos B/fisiología , Sitios de Unión , Disponibilidad Biológica , Adhesión Celular/efectos de los fármacos , Línea Celular , Humanos , Masculino , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacocinética , Sulfuros/farmacologíaRESUMEN
The interaction of LFA-1 and ICAM-1 plays an important role in the cell adhesion process. On the basis of previously reported SAR and structural information on the binding of our p-arylthiocinnamide series to LFA-1, we have identified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacokinetic profiles of the leading compounds resulted from this modification. One of the best compounds (11f) is also shown to reduce myocardial infarct size in rat.
Asunto(s)
Cinamatos/síntesis química , Molécula 1 de Adhesión Intercelular/metabolismo , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Ácidos Nipecóticos/síntesis química , Sulfuros/síntesis química , Amidas/síntesis química , Amidas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Fármacos Cardiovasculares/síntesis química , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular , Cinamatos/química , Cinamatos/farmacocinética , Cinamatos/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Infarto del Miocardio/patología , Miocardio/patología , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/farmacología , Ratas , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacocinética , Sulfuros/farmacologíaRESUMEN
[reaction: see text] The condensation of allylic diols with unsymmetrical ketones proceeds with high stereoselection to form 2,2-disubstituted 4-acyltetrahydrofurans when the alpha-substituents of the ketone differ substantially in size. A Prins-pinacol condensation of this type is the central strategic step in an enantioselective synthesis of (-)-citreoviral.
Asunto(s)
Aurovertinas/síntesis química , Furanos/síntesis química , Micotoxinas/síntesis química , Neurotoxinas/síntesis química , EstereoisomerismoRESUMEN
We report initial results of the first flight of the Antarctic Impulsive Transient Antenna (ANITA-1) 2006-2007 Long Duration Balloon flight, which searched for evidence of a diffuse flux of cosmic neutrinos above energies of E(nu) approximately 3 x 10(18) eV. ANITA-1 flew for 35 days looking for radio impulses due to the Askaryan effect in neutrino-induced electromagnetic showers within the Antarctic ice sheets. We report here on our initial analysis, which was performed as a blind search of the data. No neutrino candidates are seen, with no detected physics background. We set model-independent limits based on this result. Upper limits derived from our analysis rule out the highest cosmogenic neutrino models. In a background horizontal-polarization channel, we also detect six events consistent with radio impulses from ultrahigh energy extensive air showers.
RESUMEN
Potent and selective adamantane sulfone and sulfonamide inhibitors of 11-beta-HSD-1 have been discovered. Selected compounds from these series have robust pharmacokinetic profiles and strongly inhibit liver, fat, and brain HSD1 for extended periods after oral dosing.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Tejido Adiposo/enzimología , Animales , Encéfalo/enzimología , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Humanos , Indicadores y Reactivos , Hígado/enzimología , Ratones , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , Adamantano/síntesis química , Alquilación , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Éteres/síntesis química , Éteres/farmacología , Semivida , Humanos , Indicadores y Reactivos , Ratones , Ratones Noqueados , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Modelos MolecularesRESUMEN
We report on observations of coherent, impulsive radio Cherenkov radiation from electromagnetic showers in solid ice. This is the first observation of the Askaryan effect in ice. As part of the complete validation process for the ANITA experiment, we performed an experiment at the Stanford Linear Accelerator Center in June 2006 using a 7.5 metric ton ice target. We measure for the first time the large-scale angular dependence of the radiation pattern, a major factor in determining the solid-angle acceptance of ultrahigh-energy neutrino detectors.
RESUMEN
A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Adamantano/química , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Síndrome Metabólico/tratamiento farmacológico , Carbenoxolona/química , Carbenoxolona/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Conformación Molecular , Piperazinas/química , Piperazinas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
A series of potent and selective adamantane aminoamide 11-beta-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-activity relationship studies resulted in the discovery of dual human and mouse 11-beta-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Cianuros/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of metabolically stable adamantane amide 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity and good pharmacokinetic and pharmacodynamic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/síntesis química , Adamantano/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Adamantano/química , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Lactamas/farmacología , Administración Oral , Animales , Humanos , Lactamas/administración & dosificación , Lactamas/síntesis química , Lactamas/farmacocinética , Síndrome Metabólico/tratamiento farmacológico , RatonesRESUMEN
We report new limits on cosmic neutrino fluxes from the test flight of the Antarctic Impulsive Transient Antenna (ANITA) experiment, which completed an 18.4 day flight of a prototype long-duration balloon payload, called ANITA-lite, in early 2004. We search for impulsive events that could be associated with ultrahigh energy neutrino interactions in the ice and derive limits that constrain several models for ultrahigh energy neutrino fluxes and rule out the long-standing -burst model.
RESUMEN
The first total syntheses of higher-order members of the polypyrrolidinoindoline alkaloid family are reported. The synthesis of quadrigemine C (1) and psycholeine (3) begins with synthetic meso-chimonanthine (4), which is synthesized from commercially available oxindole and isatin in 13 steps and 35% overall yield. Double Stille cross coupling of diiodide 7, available in three steps from 4, with vinylstannane 8 produces dibutenanilide 9. Double catalytic asymmetric Heck cyclization of 9 simultaneously installs the two peripheral quaternary stereocenters and desymmetrizes this advanced meso precursor to deliver the chiral, decacyclic intermediate 11 in 62% yield and 90% ee. In two additional steps, 11 is converted to 1, which upon treatment with acid generates 3. The synthesis of quadrigemine C (1), which rigorously confirms its relative and absolute configuration, was executed in 19 linear steps (2% overall yield) from commercially available starting materials.