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1.
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
2.
Eur J Cancer ; 46(5): 966-73, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20061137

RESUMEN

The blood protein plasminogen is proteolytically cleaved to produce angiostatin and kringle 5 (K5), both of which are known angiogenesis inhibitors. A common structural element between K5, angiostatin and other endogenous angiogenesis inhibitors is the presence of the kringle protein-interacting domain. Another kringle domain-containing protein, hepatocyte growth factor (HGF), promotes angiogenesis by binding to and stimulating the tyrosine kinase receptor Met. HGF binding to Met is dependent on the kringle domains of HGF. Because both K5 and HGF contain kringle motifs and because these proteins have opposite effects on angiogenesis, we hypothesised that K5 can antagonise HGF-mediated signalling in a Met-dependent manner. We determined that K5 binding to H1299 cells is competed by HGF suggesting that these two proteins bind to the same protein. Purified K5 immunoprecipitates with Met and this interaction is abolished by increasing doses of HGF. Using proliferation, phosphorylation of Met and Akt as markers of HGF activity, we determined that K5 inhibits HGF-mediated signalling. Taken together, these data support a model by which K5 binds to Met and functions as a competitive antagonist of HGF signalling and presents a novel mechanism of action of K5.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Factor de Crecimiento de Hepatocito/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Plasminógeno/farmacología , Animales , Humanos , Pichia , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Conejos , Proteínas Recombinantes/farmacología
3.
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
4.
J Biol Chem ; 282(31): 22765-74, 2007 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-17550900

RESUMEN

The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirus-mediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor gamma coactivator 1 beta, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice.


Asunto(s)
Regulación Enzimológica de la Expresión Génica , Glucosa/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Transactivadores/biosíntesis , Triglicéridos/sangre , Adenoviridae/genética , Adenoviridae/metabolismo , Alimentación Animal , Animales , Cartilla de ADN/química , Ratones , Ratones Obesos , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fosforilación , Factores de Transcripción , Triglicéridos/metabolismo
5.
Front Biosci ; 12: 3781-94, 2007 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-17485339

RESUMEN

Stearoyl-CoA desaturases (SCDs) catalyze the biosynthesis of monounsaturated fatty acids from saturated fatty acids. Four scd genes have been identified in mice and three in human (including one pseudogene). Among the four mouse SCD isoforms, SCD1 is predominantly expressed in liver and adipose tissue. Mice null for the scd1 gene have reduced adiposity, increased energy expenditure and altered lipid profiles. To further evaluate the specific role of hepatic SCD1 and the potential to achieve similar desirable phenotypic changes in adult obese mice, adenovirus-mediated short hairpin interfering RNA (shRNA) was used to acutely knock down hepatic scd1 expression in ob/ob mice. Robust reductions in hepatic SCD1 mRNA and SCD1 enzymatic activity were achieved, sustained up to 2 weeks. Reduced hepatic content of neutral lipids and robust lowering of lipid desaturation indexes, but increased content of liver phosphotidylcholine were observed with SCD1 knockdown. Increased total plasma cholesterol levels were also observed. No significant changes in body weight were observed. Expression levels of several lipogenic and lipid oxidation genes were not significantly altered by short term SCD1 reduction, but UCP2 expression was increased. Our results demonstrate that significant changes to both hepatic and systemic lipid profiles can be achieved through specific knockdown of liver-expressed SCD1 in the ob/ob mouse model. However, hepatic SCD1 knockdown does not result in significant changes in body weight in the short term.


Asunto(s)
Ácidos Grasos/química , Lípidos/química , Hígado/enzimología , Obesidad/enzimología , Interferencia de ARN , Estearoil-CoA Desaturasa/metabolismo , Animales , Ratones , Obesidad/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
Bioorg Med Chem Lett ; 16(10): 2621-7, 2006 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-16524729

RESUMEN

Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.


Asunto(s)
Quinazolinas/química , Quinazolinas/farmacología , Quinolonas/química , Quinolonas/farmacología , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Animales , Ratones , Quinazolinas/farmacocinética , Quinolonas/farmacocinética
13.
Int J Biochem Cell Biol ; 38(8): 1290-9, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16524757

RESUMEN

Melanin-concentrating hormone (MCH), an orexigenic neuropeptide in mammals, activates a G-protein coupled receptor, MCHR1. It is expected that antagonists of MCHR1 function will prove therapeutically useful as anti-obesity agents. Intracellular signaling by MCHR1 has been investigated primarily using non-neural cell lines expressing the recombinant receptor, in which MCHR1 has been shown to couple to G alpha(i/o) and G alpha(q) G-proteins. While these cell lines have been widely utilized to discover and optimize small molecule antagonists, it is unknown whether the intracellular signaling pathways in these cells accurately reflect those in neurons. Thus, we sought to develop a neurally derived cell line endogenously expressing MCHR1. IMR32, a human neuroblastoma cell line, has been shown to express MCHR1 mRNA; however, we were unable to detect either MCH-binding or MCH-stimulated Ca++-mobilization in these cells. Following transfection of IMR32 cells with a plasmid encoding human G alpha(16) G-protein, we isolated a cell line, I3.4.2, which responded to MCH in Ca++-mobilization assays. We found that the expression level of MCHR1 mRNA in I3.4.2 cells was 2000-fold higher than in the parent cell line. Using [125I]MCH saturation-binding to I3.4.2 cell membranes, we estimated the Bmax as 0.72 pmol/mg protein and the Kd as 0.35 nM. We report that Ca++-mobilization in I3.4.2 cells was insensitive to pertussis toxin (Ptx) treatment, indicating that signaling was via G alpha(q) G-proteins. Furthermore, negative results in cAMP accumulation assays confirmed the lack of signaling via the G alpha(i/o) G-proteins. Our results suggest that the I3.4.2 cell line may be useful for characterization of MCHR1 activity in a neural-derived cell line.


Asunto(s)
Neuronas/metabolismo , Receptores de Somatostatina/metabolismo , Animales , Células CHO , Calcio/metabolismo , Línea Celular Tumoral , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Proteínas de Unión al GTP/metabolismo , Humanos , Hormonas Hipotalámicas/metabolismo , Hormonas Hipotalámicas/farmacología , Melaninas/metabolismo , Melaninas/farmacología , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología , Neuronas/patología , Toxina del Pertussis/farmacología , Hormonas Hipofisarias/metabolismo , Hormonas Hipofisarias/farmacología , Unión Proteica , Receptores de Somatostatina/genética , Receptores de Somatostatina/fisiología , Transducción de Señal/efectos de los fármacos , Transfección
14.
Bioorg Med Chem Lett ; 15(23): 5293-7, 2005 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16203136

RESUMEN

The synthesis and biological evaluation of novel 3-amino indazole melanin concentrating hormone receptor-1 antagonists are reported, several of which demonstrated functional activity of less than 100nM. Compounds 19 and 28, two of the more potent compounds identified in this study, were characterized by high exposure in the brain and demonstrated robust efficacy when dosed in diet-induced obese mice.


Asunto(s)
Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Indazoles/síntesis química , Indazoles/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/administración & dosificación , Humanos , Indazoles/administración & dosificación , Ratones , Piperidinas/química , Distribución Tisular
15.
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
17.
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
18.
J Med Chem ; 48(5): 1318-21, 2005 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-15743174

RESUMEN

Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.


Asunto(s)
Acetamidas/síntesis química , Fármacos Antiobesidad/síntesis química , Indazoles/síntesis química , Obesidad/tratamiento farmacológico , Pirrolidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Acetamidas/farmacocinética , Acetamidas/farmacología , Administración Oral , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Unión Competitiva , Encéfalo/metabolismo , Calcio/metabolismo , Enfermedad Crónica , Indazoles/farmacocinética , Indazoles/farmacología , Ratones , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Distribución Tisular
19.
Bioorg Med Chem Lett ; 14(19): 4873-7, 2004 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-15341942

RESUMEN

A high-throughput screen was performed in order to identify chemotypes that are bound by the melanin concentrating hormone receptor-1 (MCHr1). A novel 2-amino-8-alkoxyquinoline compound (1) was identified and subsequently optimized using a parallel and automated procedure for the rapid production of multiple analogs. The structure-activity relationships that emerged from this effort are described, along with selected pharmacokinetic parameters of compound (d)-61 when dosed orally in diet-induced obese mice.


Asunto(s)
Fármacos Antiobesidad/síntesis química , Quinolinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Ratones , Quinolinas/metabolismo , Quinolinas/farmacología , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad
20.
Bioorg Med Chem Lett ; 14(19): 4879-82, 2004 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-15341943

RESUMEN

The continued SAR investigation of 2-amino-8-alkoxy quinolines as melanin concentrating hormone receptor-1 (MCHr1) antagonists is reported. Prior hit-to-lead efforts resulted in the identification of 1 as a robust MCHr1 antagonist. Further delineation of the structural parameters essential for MCHr1-binding affinity of this class of nontraditional GPCR ligands resulted in the identification of compounds such as 33, 34 and 37, which demonstrate single digit nanomolar antagonism of MCHr1-mediated Ca(2+) release. The synthesis and biological evaluation of these compounds are reported.


Asunto(s)
Fármacos Antiobesidad/síntesis química , Quinolinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Ratones , Quinolinas/metabolismo , Quinolinas/farmacología , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad
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