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2.
Front Endocrinol (Lausanne) ; 12: 652628, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054727

RESUMO

The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and ß-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated ß-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function in vitro and in vivo. GRK inhibition is a potential therapeutic approach to enhance endogenous and pharmacologically stimulated GLP-1R signaling.


Assuntos
Receptor Quinase 1 Acoplada a Proteína G/antagonistas & inibidores , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Amidas/química , Animais , Células CHO , Cálcio/metabolismo , Cricetulus , Diabetes Mellitus/metabolismo , Dipeptidil Peptidase 4/metabolismo , Ingestão de Alimentos , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Camundongos , Obesidade/metabolismo , Fosforilação , Receptores de Glucagon/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , beta-Arrestinas/metabolismo
3.
Transl Lung Cancer Res ; 10(11): 4235-4249, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35004253

RESUMO

BACKGROUND: This study aimed to verify the feasibility of human epidermal growth factor receptor-2 (HER2) amplification detection by digital polymerase chain reaction (dPCR) in non-small cell lung cancer (NSCLC) patients and explore whether HER2 amplification could be detected in circulating tumor DNA (ctDNA) by dPCR. METHODS: A total of 112 fresh biopsy tissues and 88 blood samples from NSCLC patients were collected. The serum ctDNA was obtained from blood samples. The copy number of the HER2 gene was evaluated by dPCR and next-generation sequencing (NGS). The sensitivity/specificity and survival analysis were performed by the receiver operating characteristic (ROC) curve. The survival analysis was performed by Kaplan-Meier (KM) curve and univariate Cox regression analysis was also conducted. RESULTS: ROC analysis showed a good prediction result for HER2 amplification in blood samples by dPCR. The survival analysis showed that the median overall survival (OS) in the HER2 negative group detected by blood dPCR was significantly different from the positive group. The results of multivariate Cox regression were the same as those of survival analysis. CONCLUSIONS: Blood dPCR might be a potential method to detect HER2 amplification in NSCLC. Amplification of the HER2 gene detected by dPCR was correlated with OS in NSCLC.

4.
Bioorg Med Chem Lett ; 30(23): 127602, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038544

RESUMO

G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of ß-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.


Assuntos
Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Ensaios Enzimáticos , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Ftalazinas/síntese química , Ftalazinas/farmacocinética , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 30(17): 127387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738984

RESUMO

(2S,3R,4R,5S,6R)-2-Aryl-5,5-difluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols and (2S,3R,4R,5S,6R)-2-aryl-5-fluoro-5-methyl-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diols were discovered as dual inhibitors of sodium glucose co-transporter proteins (e.g. SGLT1 and SGLT2) through rational drug design, efficient synthesis, and in vitro and in vivo evaluation. Compound 6g demonstrated potent dual inhibitory activities (IC50 = 96 nM for SGLT1 and IC50 = 1.3 nM for SGLT2). It showed robust inhibition of blood glucose excursion in an oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats when dosed at both 1 mg/kg and 10 mg/kg orally. It also demonstrated postprandial glucose control in db/db mice when dosed orally at 10 mg/kg.


Assuntos
Glucosídeos/química , Hipoglicemiantes/química , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Transportador 2 de Glucose-Sódio/química , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Glicemia/análise , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Desenho de Fármacos , Teste de Tolerância a Glucose , Glucosídeos/metabolismo , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Meia-Vida , Halogenação , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Microssomos/metabolismo , Ratos , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio/metabolismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 28(21): 3446-3453, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30268701

RESUMO

A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50 = 43 nM for SGLT1 and IC50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg.


Assuntos
Desoxiglucose/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Desoxiglucose/análogos & derivados , Desoxiglucose/síntese química , Desenho de Fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Macaca fascicularis , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos Sprague-Dawley , Ratos Zucker , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/síntese química , Inibidores do Transportador 2 de Sódio-Glicose/química , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 28(7): 1182-1187, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29523385

RESUMO

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.


Assuntos
Derivados de Benzeno/farmacologia , Ciclobutanos/farmacologia , Glicosídeos/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Administração Oral , Animais , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/química , Ciclobutanos/administração & dosagem , Ciclobutanos/química , Cães , Relação Dose-Resposta a Droga , Glicosídeos/administração & dosagem , Glicosídeos/química , Haplorrinos , Humanos , Camundongos , Estrutura Molecular , Ratos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 28(4): 720-726, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29366647

RESUMO

Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.


Assuntos
Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Benzofuranos/farmacologia , Compostos de Bifenilo/farmacologia , Células CHO , Cricetulus , Cães , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucuronídeos/biossíntese , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenilpropionatos/farmacologia , Piperidinas/farmacologia , Pirazinas/síntese química , Pirazinas/química , Pirazinas/metabolismo , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologia
9.
PLoS One ; 7(2): e30555, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22355316

RESUMO

BACKGROUND: Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM). METHODS: (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; (3)H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RT(G)) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity. RESULTS: Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G). Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio. CONCLUSIONS: Canagliflozin lowered RT(G) and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.


Assuntos
Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Hiperglicemia/tratamento farmacológico , Rim/fisiopatologia , Tiofenos/uso terapêutico , Animais , Células CHO , Canagliflozina , Células Cultivadas , Cricetinae , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Zucker , Proteínas de Transporte de Sódio-Glucose/genética , Proteínas de Transporte de Sódio-Glucose/metabolismo , Transportador 1 de Glucose-Sódio/genética , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Aumento de Peso/efeitos dos fármacos
10.
Bioorg Med Chem ; 16(6): 3321-41, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18155554

RESUMO

Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.


Assuntos
PPAR alfa/agonistas , PPAR delta/agonistas , Tiadiazóis/química , Tiadiazóis/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Regulação da Expressão Gênica/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Camundongos , Tiadiazóis/síntese química , Tiadiazóis/farmacocinética , Ativação Transcricional
11.
Bioorg Med Chem Lett ; 17(24): 6773-8, 2007 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-18029176

RESUMO

A series of aminoindane derivatives were synthesized and shown to be potent PPARalpha agonists. The compounds were obtained as racemates in 12 steps, and tested for PPARalpha activation and PPARalpha mediated induction of the HD gene. SAR was developed by variation to the core structure as shown within. Oral bioavailability was demonstrated in a Sprague-Dawley rat, while efficacy to reduce plasma triglycerides and plasma glucose was demonstrated in db/db mice.


Assuntos
Butiratos/síntese química , Butiratos/farmacologia , Indanos/síntese química , Indanos/farmacologia , PPAR alfa/agonistas , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Aminoácidos/química , Animais , Butiratos/química , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Indanos/química , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/química
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