RESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Piperazinas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Adamantano/farmacocinética , Animais , Linhagem Celular , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Piperazinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Tecido Adiposo/enzimologia , Animais , Encéfalo/enzimologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Humanos , Indicadores e Reagentes , Fígado/enzimologia , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Adamantano/síntese química , Alquilação , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Éteres/síntese química , Éteres/farmacologia , Meia-Vida , Humanos , Indicadores e Reagentes , Camundongos , Camundongos Knockout , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Modelos MolecularesRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Adamantano/farmacologia , Cianetos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Carbenoxolona/química , Carbenoxolona/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Conformação Molecular , Piperazinas/química , Piperazinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Adamantano/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Adamantano/química , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Adamantano/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Adamantano/química , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Conformação Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Lactamas/farmacologia , Administração Oral , Animais , Humanos , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/farmacocinética , Síndrome Metabólica/tratamento farmacológico , CamundongosRESUMO
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.
RESUMO
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.
Assuntos
Benzilaminas/síntese química , Hipoglicemiantes/síntese química , Receptores de Glucocorticoides/antagonistas & inibidores , Sulfonamidas/síntese química , Fosfatase Alcalina/biossíntese , Fosfatase Alcalina/genética , Animais , Benzilaminas/efeitos adversos , Benzilaminas/farmacologia , Células Cultivadas , Cricetinae , Cricetulus , Dexametasona/farmacologia , Feminino , Genes Reporter , Glucocorticoides/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Camundongos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Gravidez , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Tirosina Transaminase/biossíntese , Útero/efeitos dos fármacosRESUMO
The optimization of a series of nonsteroidal glucocorticoid modulators is reported. Potent selective GR ligands that have improved metabolic stability were discovered typified by the subnanomolar acid 12 (GR binding IC(50)=0.6 nM).
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Humanos , Ligantes , Ligação Proteica , Receptores de Glucocorticoides/metabolismoRESUMO
The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator-statin hybrids is reported. Potent steroidal antagonist-statin hybrids like 22 (h-GR binding IC(50)=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC(50)=2 nM) were discovered. Appending a 'statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Receptores de Glucocorticoides/efeitos dos fármacos , Meia-Vida , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/químicaRESUMO
Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved.
Assuntos
Ácidos e Sais Biliares/química , Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Ácidos e Sais Biliares/farmacocinética , Disponibilidade Biológica , Ratos , Ratos Sprague-DawleyRESUMO
A new class of selective nonsteroidal glucocorticoid receptor modulators typified by N-[3-[benzyl-(4-chloro-2-fluoro-benzyl)-amino]-2-methyl-phenyl]-methanesulfonamide 19 has been discovered.
Assuntos
Receptores de Glucocorticoides/efeitos dos fármacos , Animais , Compostos de Benzil , Humanos , Ratos , Relação Estrutura-Atividade , SulfonamidasRESUMO
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.
Assuntos
Sistemas de Liberação de Medicamentos , Glucuronídeos/metabolismo , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Fígado/efeitos dos fármacos , Mifepristona/administração & dosagem , Mifepristona/farmacologia , Receptores de Glucocorticoides/antagonistas & inibidores , Administração Oral , Fosfatase Alcalina/antagonistas & inibidores , Animais , Ligação Competitiva/efeitos dos fármacos , Dexametasona/farmacocinética , Circulação Êntero-Hepática , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucocorticoides/farmacocinética , Glucuronídeos/farmacocinética , Antagonistas de Hormônios/farmacocinética , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Injeções Intravenosas , Microssomos Hepáticos/metabolismo , Mifepristona/farmacocinética , Compostos de Amônio Quaternário , Ratos , Ratos Sprague-Dawley , Tirosina Transaminase/antagonistas & inibidoresRESUMO
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.