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1.
Amino Acids ; 47(5): 917-24, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25618754

RESUMO

Leucine is an essential branched-chain amino acid that acts as a substrate for protein synthesis and as a signaling molecule. Leucine not incorporated into muscle protein is ultimately oxidized through intermediates such as ß-hydroxy-ß-methylbutyrate (HMB) which itself is reported to enhance muscle mass and function in rats and humans. HMB has been reported in the plasma following oral leucine administration in sheep and pigs but not in Sprague-Dawley rats, the standard preclinical model. Therefore, we conducted radiolabeled absorption, distribution, metabolism and excretion (ADME) studies in rats using a low (3 mg/kg) or high dose (1,000 mg/kg) of (14)C-leucine. Blood, tissue, and urine samples were analyzed for (14)C-leucine and its metabolites by HPLC-MS. Our results show for the first time that (14)C-HMB appears in plasma and urine of rats following an oral dose of (14)C-leucine. (14)C-leucine appears in plasma as (14)C-α-ketoisocaproic acid (KIC) with a slower time course than (14)C-HMB, a putative product of KIC. Further, two novel metabolites of leucine were detected in urine, N-acetyl leucine and glycyl leucine. Mass balance studies demonstrate that excretory routes accounted for no more than 0.9 % of the radiolabel and approximately 61 % of the dose was recovered in the carcass. Approximately 65 % of the dose was recovered in total, suggesting that approximately one-third of the leucine dose is oxidized to CO2. In conclusion, this study demonstrates endogenous production of HMB from leucine in adult rats, a standard preclinical model used to guide design of clinical trials in nutrition.


Assuntos
Dipeptídeos/urina , Cetoácidos/sangue , Leucina/análogos & derivados , Leucina/farmacocinética , Valeratos/sangue , Animais , Transporte Biológico , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Dipeptídeos/sangue , Absorção Intestinal/fisiologia , Cetoácidos/urina , Leucina/sangue , Leucina/urina , Masculino , Espectrometria de Massas , Oxirredução , Ratos , Ratos Sprague-Dawley , Valeratos/urina
2.
Bioorg Med Chem Lett ; 17(8): 2365-71, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17350253

RESUMO

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.


Assuntos
Amidas/farmacologia , Cromonas/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Obesidade/tratamento farmacológico , Técnicas de Patch-Clamp , Farmacocinética
3.
Bioorg Med Chem Lett ; 17(4): 884-9, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17188866

RESUMO

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.


Assuntos
Cromonas/síntese química , Cromonas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/farmacologia , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Dieta , Gorduras na Dieta , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Fenfluramina/farmacologia , Indicadores e Reagentes , Camundongos , Conformação Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Relação Estrutura-Atividade
4.
J Med Chem ; 49(22): 6569-84, 2006 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-17064075

RESUMO

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.


Assuntos
Benzodioxóis/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Cromonas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Acilação , Animais , Área Sob a Curva , Benzodioxóis/farmacocinética , Benzodioxóis/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular , Cromonas/farmacocinética , Cromonas/toxicidade , Cães , Eletrocardiografia/efeitos dos fármacos , Feminino , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Indicadores e Reagentes , Camundongos , Camundongos Endogâmicos C57BL , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
5.
6.
J Med Chem ; 49(15): 4459-69, 2006 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16854051

RESUMO

The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.


Assuntos
Aminopiridinas/síntese química , Fármacos Antiobesidade/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacologia , Aminopiridinas/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/síntese química , Depressores do Apetite/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Cristalografia por Raios X , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores de Grelina , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia
7.
Endocrine ; 29(2): 375-81, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16785615

RESUMO

Dexfenfluramine (DEX) and sibutramine (SIB) are effective antiobesity agents. Their effects on weight control and hormone profile have not been previously studied in diet-switched diet-induced obese (DIO) mice, in which treatment is initiated upon cessation of a low-fat diet and resumption of a high-fat diet. Furthermore, their effects on circulating ghrelin in obese humans or in animal models of obesity have not yet been reported. Male C57Bl/6J DIO mice after 16 wk on a high-fat diet (HF, 60 kcal% fat) were switched to a low-fat diet (LF, 10 kcal% fat) for 50 d. HF diet resumed concurrently with treatment for 28 d with DEX 3 and 10 mg/kg, twice a day (BID); SIB 5 mg/kg BID; or vehicle. Rapid weight regain ensued in vehicle-treated DIO mice. DEX or SIB treatment significantly blunted the body weight gain. Caloric intake was decreased acutely by DEX or SIB vs vehicle during the first 2 d treatment, but returned to control after 5 d. At the end of study, epididymal fat weight and whole body fat mass determined by DEXA scan were decreased by DEX 10 mg/kg, and whole body lean mass decreased with DEX 3 mg/kg treatment. Circulating ghrelin on d 28 was increased with either DEX 3 or 10 mg/kg treatment, while growth hormone and insulin were decreased. Leptin was also decreased in the DEX 10 mg/kg group. SIB did not significantly affect fat mass, ghrelin, growth hormone, insulin, or leptin. Mice chronically fed LF diet maintained a lower caloric intake, gained less weight and fat mass than diet-switched mice, and had higher ghrelin and lower insulin and leptin. In summary, weight regain in diet-switched DIO mice is delayed with either DEX or SIB treatment. DEX treatment of diet-switched DIO mice decreased growth hormone, insulin, leptin, fat mass, lean mass, and increased ghrelin, while SIB only decreased body weight.


Assuntos
Fármacos Antiobesidade/farmacologia , Ciclobutanos/farmacologia , Dexfenfluramina/farmacologia , Obesidade/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Dieta com Restrição de Gorduras , Grelina , Hormônio do Crescimento/sangue , Masculino , Camundongos , Obesidade/etiologia , Obesidade/prevenção & controle , Hormônios Peptídicos/sangue , Magreza/sangue , Aumento de Peso/efeitos dos fármacos
8.
J Med Chem ; 49(8): 2568-78, 2006 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-16610800

RESUMO

Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides resulted in weight loss and food intake decrease in rodents. Here we report the effects of GHS-R antagonists, some of which were potent, selective, and orally bioavailable. A structure-activity relationship study led to the discovery of 8a, which was effective in decreasing food intake and body weight in several acute rat studies.


Assuntos
Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores de Grelina , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Tempo
9.
Bioorg Med Chem Lett ; 15(23): 5293-7, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16203136

RESUMO

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.


Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Indazóis/síntese química , Indazóis/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Humanos , Indazóis/administração & dosagem , Camundongos , Piperidinas/química , Distribuição Tecidual
10.
J Med Chem ; 48(19): 5888-91, 2005 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-16161992

RESUMO

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.


Assuntos
Cumarínicos/síntese química , Piperidinas/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Cumarínicos/efeitos adversos , Cumarínicos/farmacologia , Cães , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético , Humanos , Masculino , Camundongos , Camundongos Obesos , Contração Miocárdica/efeitos dos fármacos , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 15(11): 2752-7, 2005 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-15911251

RESUMO

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.


Assuntos
Indazóis/síntese química , Indazóis/farmacologia , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Ureia/química , Animais , Indazóis/química , Indazóis/uso terapêutico , Camundongos , Relação Estrutura-Atividade
13.
J Med Chem ; 48(5): 1318-21, 2005 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-15743174

RESUMO

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.


Assuntos
Acetamidas/síntese química , Fármacos Antiobesidade/síntese química , Indazóis/síntese química , Obesidade/tratamento farmacológico , Pirrolidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Ligação Competitiva , Encéfalo/metabolismo , Cálcio/metabolismo , Doença Crônica , Indazóis/farmacocinética , Indazóis/farmacologia , Camundongos , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade , Distribuição Tecidual
14.
Eur J Pharmacol ; 487(1-3): 183-97, 2004 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-15033391

RESUMO

Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3) receptors regulate release of histamine and other neurotransmitters, and histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H(3) receptor antagonist which binds potently and selectively to both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H(3) receptor antagonist, A-331440, has potential as an antiobesity agent.


Assuntos
Fármacos Antiobesidade/farmacologia , Compostos de Bifenilo/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Nitrilas/farmacologia , Pirrolidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Depressores do Apetite/farmacologia , Comportamento Animal/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Clonagem Molecular , Diagnóstico por Imagem , Dieta , Gorduras na Dieta/farmacologia , Fenfluramina/farmacologia , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Ensaio Radioligante , Ratos , Redução de Peso/efeitos dos fármacos
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