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1.
J Am Assoc Lab Anim Sci ; 53(3): 246-60, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24827566

RESUMEN

Environmental enrichment in rodents may improve animal well-being but can affect neurologic development, immune system function, and aging. We tested the hypothesis that wood block enrichment affects the interpretation of traditional and transcriptomic endpoints in an exploratory toxicology testing model using a well-characterized reference compound, cyclophosphamide. ANOVA was performed to distinguish effects of wood block enrichment separate from effects of 40 mg/kg cyclophosphamide treatment. Biologically relevant and statistically significant effects of wood block enrichment occurred only for body weight gain. ANOVA demonstrated the expected effects of cyclophosphamide on food consumption, spleen weight, and hematology. According to transcriptomic endpoints, cyclophosphamide induced fewer changes in gene expression in liver than in spleen. Splenic transcriptomic pathways affected by cyclophosphamide included: iron hemostasis; vascular tissue angiotensin system; hepatic stellate cell activation and fibrosis; complement activation; TGFß-induced hypertrophy and fibrosis; monocytes, macrophages, and atherosclerosis; and platelet activation. Changes in these pathways due to cyclophosphamide treatment were consistent with bone marrow toxicity regardless of enrichment. In a second study, neither enrichment nor type of cage flooring altered body weight or food consumption over a 28-d period after the first week. In conclusion, wood block enrichment did not interfere with a typical exploratory toxicology study; the effects of ingested wood on drug level kinetics may require further consideration.


Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Ciclofosfamida/administración & dosificación , Ratas , Toxicología/métodos , Administración Oral , Animales , Animales de Laboratorio , Peso Corporal/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Madera
2.
Nat Med ; 19(2): 202-8, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23291630

RESUMEN

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.


Asunto(s)
Antineoplásicos/farmacología , Plaquetas/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Neoplasias Hematológicas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Perros , Femenino , Células HeLa , Humanos , Ratones , Ratones SCID , Proteínas Proto-Oncogénicas c-bcl-2/química , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína bcl-X/antagonistas & inhibidores
3.
Life Sci ; 91(13-14): 583-6, 2012 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-22406077

RESUMEN

AIMS: Endothelin receptor A (ET(A)) antagonism normalizes fetal growth in several models of rodent fetal growth restriction (FGR). Our aims were to determine the levels of ET(A) antagonist in maternal and fetal plasma following chronic maternal administration, and to determine its impact on pregnancy outcome, survival and growth of rat pups. MAIN METHODS: Timed pregnant rats were treated with one of two endothelin receptor antagonists or vehicle, from gestation day 14-21 (term=22 days). The antagonists and their respective doses were ABT-546 (20mg/kg/day) and FR139317 (12 mg/kg/day). On day 21, in six rats per group, maternal and fetal plasma ABT-546 was assayed by HPLC. Five additional rats in each group delivered spontaneously and nursed their pups through postpartum day 7. Viability of newborns, oxygen saturation, litter sizes, and pup weights were recorded on postpartum days 1 and 7. KEY FINDINGS: Fetal antagonist levels reached only 2% of maternal levels (p<0.01). There were no significant differences among groups in length of gestation; litter size; survival, number and weight of live pups at birth and at 7 days postpartum; and tissue oxygen saturation. SIGNIFICANCE: Maternal administration of an ET(A) antagonist, at a dose sufficient to ameliorate FGR, has no adverse impact on survival and growth of neonatal rat pups. ET(A) antagonism, delivered maternally, produces sufficiently low fetal plasma levels of antagonist so as not to present a survival threat to the neonatal pups. The beneficial effects of maternally administered ET(A) antagonism on fetal growth occur in the maternal, not the fetal, compartment.


Asunto(s)
Azepinas/farmacología , Antagonistas de los Receptores de la Endotelina A , Desarrollo Fetal/efectos de los fármacos , Indoles/farmacología , Pirrolidinas/farmacología , Animales , Animales Recién Nacidos , Azepinas/administración & dosificación , Azepinas/farmacocinética , Femenino , Retardo del Crecimiento Fetal/prevención & control , Indoles/administración & dosificación , Indoles/farmacocinética , Intercambio Materno-Fetal , Embarazo , Resultado del Embarazo , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacocinética , Ratas , Ratas Sprague-Dawley
4.
J Med Chem ; 55(4): 1751-7, 2012 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-22263872

RESUMEN

A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Bases de Datos Factuales , Diacilglicerol O-Acetiltransferasa/química , Perros , Femenino , Hurones , Tránsito Gastrointestinal/efectos de los fármacos , Células HeLa , Hemodinámica/efectos de los fármacos , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Periodo Posprandial , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-Actividad , Triglicéridos/sangre , Vómitos/inducido químicamente
5.
Cancer Chemother Pharmacol ; 65(3): 419-25, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19526240

RESUMEN

PURPOSE: ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration. METHODS: ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods. RESULTS: The CSF penetration of ABT-888 was 57+/-7% (mean+/-SD). The peak ABT-888 concentration in the plasma was 0.62+/-0.18 microM. Plasma and CSF AUC0-infinity were 3.7+/-1.7 and 2.1+/-0.8 microM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration. CONCLUSION: The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans.


Asunto(s)
Bencimidazoles/sangre , Bencimidazoles/líquido cefalorraquídeo , Administración Oral , Animales , Área Bajo la Curva , Bencimidazoles/farmacocinética , Humanos , Leucocitos Mononucleares/enzimología , Macaca mulatta , Masculino , Tasa de Depuración Metabólica , Estructura Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/metabolismo , Factores de Tiempo
6.
J Med Chem ; 51(3): 380-3, 2008 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-18183944

RESUMEN

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.


Asunto(s)
Fármacos Antiobesidad/síntesis química , Cicloheptanos/síntesis química , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Hipolipemiantes/síntesis química , Cetoácidos/síntesis química , Urea/análogos & derivados , Urea/síntesis química , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Cicloheptanos/farmacocinética , Cicloheptanos/farmacología , Diacilglicerol O-Acetiltransferasa/genética , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Cetoácidos/farmacocinética , Cetoácidos/farmacología , Hígado/metabolismo , Ratones , Ratones Mutantes , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/metabolismo , Urea/farmacocinética , Urea/farmacología , Pérdida de Peso
7.
Bioorg Med Chem Lett ; 17(8): 2365-71, 2007 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-17350253

RESUMEN

A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series.


Asunto(s)
Amidas/farmacología , Cromonas/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Obesidad/tratamiento farmacológico , Técnicas de Placa-Clamp , Farmacocinética
8.
Bioorg Med Chem Lett ; 17(4): 874-8, 2007 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-17234405

RESUMEN

The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.


Asunto(s)
Piperidinas/síntesis química , Piperidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Alquilación , Animales , Fenómenos Químicos , Química Física , Cromonas , Reacciones Cruzadas , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Canales de Potasio Éter-A-Go-Go/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Humanos , Ratones , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 17(4): 884-9, 2007 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-17188866

RESUMEN

The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.


Asunto(s)
Cromonas/síntesis química , Cromonas/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Depresores del Apetito/farmacología , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Dieta , Grasas de la Dieta , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Fenfluramina/farmacología , Indicadores y Reactivos , Ratones , Conformación Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Relación Estructura-Actividad
10.
J Med Chem ; 49(22): 6569-84, 2006 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-17064075

RESUMEN

Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.


Asunto(s)
Benzodioxoles/farmacología , Enfermedades Cardiovasculares/inducido químicamente , Cromonas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Acilación , Animales , Área Bajo la Curva , Benzodioxoles/farmacocinética , Benzodioxoles/toxicidad , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Cromonas/farmacocinética , Cromonas/toxicidad , Perros , Electrocardiografía/efectos de los fármacos , Femenino , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Indicadores y Reactivos , Ratones , Ratones Endogámicos C57BL , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
11.
J Mol Endocrinol ; 37(1): 51-62, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16901923

RESUMEN

Ghrelin, a 28 amino acid, octanoylated peptide, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). In addition to various endocrine functions, including stimulation of GH release, ghrelin has been characterized as an important regulator of energy homeostasis. Ghrelin administration has been shown to increase adiposity in rodents and stimulate food intake in humans. Studies suggest that these orexigenic effects are mediated primarily through GHS-R expression in hypothalamic and pituitary neuronal pathways. In this context, GHS-R has been recognized as a potential target for the treatment of GH deficiency and body weight disorders. Cell lines provide convenient in vitro systems to identify and characterize potential pharmacophores and to analyze GHS-R functional activity. While recombinant cell lines that overexpress GHS-R have served as effective research tools for these studies, such cell lines may differ in signaling response to ghrelin compared with hypothalamic or pituitary cells expressing GHS-R. We show here that a cell line derived from a rat anterior pituitary adenoma, RC-4B/C, expresses endogenous GHS-R as judged by reverse transcriptase-PCR. In a Ca(2+)mobilization assay, RC-4B/C cells demonstrate a dose-dependent increase in intracellular [Ca(2+)] on stimulation with rat ghrelin and a related peptide agonist, hexarelin (EC(50), 1.0 nM and 1.7 nM respectively), but are unresponsive to treatment with inactive des-octanoyl rat ghrelin. A subclone, RC-4B/C.40, with a more robust and stable ghrelin response, was isolated from the parental population of cells to allow further analysis of GHS-R signal transduction. Using pertussis toxin and the phospholipase C inhibitor U-73122, we show that ghrelin signals through the Gq pathway in the RC-4B/C.40 cells. We also demonstrate that the ghrelin-induced rise of intracellular [Ca(2+)] in RC-4B/C.40 cells involves initial Ca(2+)release from intracellular stores followed by a sustained elevation that occurs via influx of extracellular Ca(2+) through ion channels. In addition, unlike observations reported in recombinant cell systems, the RC-4B/C.40 cells do not exhibit a high level of GHS-R constitutive activity as determined in a phosphatidylinositol hydrolysis assay. Overall, the data presented here suggest that the RC-4B/C parental and RC-4B/C.40 cells provide novel in vitro systems for the characterization of GHS-R pharmacophores and ghrelin signaling.


Asunto(s)
Hormonas Peptídicas/metabolismo , Hipófisis/citología , Receptores Acoplados a Proteínas G/metabolismo , Animales , Células CHO , Calcio/metabolismo , Línea Celular , Cricetinae , Cricetulus , Inhibidores Enzimáticos/metabolismo , Ghrelina , Humanos , Ratas , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/genética , Receptores de Ghrelina , Transducción de Señal/fisiología , Tapsigargina/metabolismo
12.
J Med Chem ; 49(7): 2339-52, 2006 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-16570930

RESUMEN

An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.


Asunto(s)
Fármacos Antiobesidad/síntesis química , Sistema Cardiovascular/efectos de los fármacos , Cromonas/síntesis química , Piperidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/sangre , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cromonas/efectos adversos , Cromonas/sangre , Perros , Indazoles/efectos adversos , Indazoles/sangre , Indazoles/síntesis química , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Miocárdica/efectos de los fármacos , Piperidinas/efectos adversos , Piperidinas/sangre , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular
13.
J Med Chem ; 48(19): 5888-91, 2005 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-16161992

RESUMEN

4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.


Asunto(s)
Cumarinas/síntesis química , Piperidinas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cumarinas/efectos adversos , Cumarinas/farmacología , Perros , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético , Humanos , Masculino , Ratones , Ratones Obesos , Contracción Miocárdica/efectos de los fármacos , Piperidinas/efectos adversos , Piperidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad
16.
Bioorg Med Chem Lett ; 15(11): 2752-7, 2005 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-15911251

RESUMEN

A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with excellent binding affinity, good functional potency, and oral efficacy in a chronic model for weight loss in diet-induced obese mice.


Asunto(s)
Indazoles/síntesis química , Indazoles/farmacología , Obesidad/tratamiento farmacológico , Receptores de Somatostatina/antagonistas & inhibidores , Urea/química , Animales , Indazoles/química , Indazoles/uso terapéutico , Ratones , Relación Estructura-Actividad
17.
Clin Sci (Lond) ; 103 Suppl 48: 112S-117S, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12193067

RESUMEN

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET(A) and ET(B) receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.


Asunto(s)
Antagonistas de los Receptores de Endotelina , Endotelio Vascular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Pirrolidinas/farmacología , Vasodilatadores/farmacología , Análisis de Varianza , Animales , Aorta , Atrasentán , Perros , Relación Dosis-Respuesta a Droga , Endotelina-1/farmacología , Femenino , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Pirrolidinas/farmacocinética , Conejos , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina A , Receptor de Endotelina B , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Vasoconstrictores/farmacología , Vasodilatadores/farmacocinética , Venenos de Víboras/farmacología
18.
Clin Sci (Lond) ; 103 Suppl 48: 418S-423S, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12193136

RESUMEN

Endothelin-1 (ET-1) is a 21-amino-acid peptide that binds to G-protein-coupled receptors to evoke biological responses. Previously we have shown that ET-1 stimulates glucose uptake in 3T3-L1 adipocytes and neonatal rat cardiomyocytes, but the mechanism is not completely understood. ET-1 is known to modulate intracellular Ca(2+) and cAMP levels. Depletion of intracellular Ca(2+) by treating 3T3-L1 adipocytes with EDTA and 1,2-bis(2-amino-5-methylphenoxy)ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxymethyl ester (MAPTAM) did not have a significant effect on ET-1-induced glucose uptake. Forskolin, a potent stimulator which stimulates adenylate cyclase and increases the intracellular cAMP level, partially inhibited insulin-stimulated glucose uptake in 3T3-L1 cells, but had no significant impact on the effect of ET-1. Forskolin also did not show an effect on the tyrosine phosphorylation of a 75 kDa protein induced by ET-1. Glucosamine treatment causes insulin resistance in cells, possibly by entering the hexosamine biosynthetic pathway. In neonatal rat cardiomyocytes, glucosamine treatment blocked both insulin and ET-1-stimulated glucose uptake and also eliminated the translocation of IRAP, an aminopeptidase in GLUT4-containing vesicles, from the cytoplasm to the plasma membrane. These results suggest that ET-1-induced glucose uptake is independent of its effects on modulating intracellular Ca(2+) and cAMP levels, but is likely linked to the hexosamine biosynthetic pathway.


Asunto(s)
Calcio/metabolismo , AMP Cíclico/metabolismo , Endotelina-1/farmacología , Glucosamina/metabolismo , Glucosa/metabolismo , Miocardio/metabolismo , Células 3T3 , Adenilil Ciclasas/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Colforsina/farmacología , Relación Dosis-Respuesta a Droga , Activadores de Enzimas/farmacología , Fibroblastos/metabolismo , Glucosamina/farmacología , Hexosaminas/biosíntesis , Insulina/farmacología , Proteína Antagonista del Receptor de Interleucina 1 , Isoproterenol/farmacología , Ratones , Ratas , Sialoglicoproteínas/metabolismo , Estimulación Química
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