Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
Bioorg Med Chem Lett ; 73: 128912, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35907607

RESUMO

We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction of the oxadiazole fragment followed by cyclization gave access to imidazopyrazines in moderate to good yields. A selection of orthoesters also allowed functionalization on the 2-position of the imidazole ring. This method afforded a variety of imidazopyrazine derivatives with varying substitution on the 2, 5 and 6 positions. Our studies suggest that both a 2-trifluoromethyl group and N-methylation are crucial for mitochondrial uncoupling capacity.


Assuntos
Mitocôndrias , Pirazinas , Ciclização , Mitocôndrias/metabolismo , Oxidiazóis/metabolismo , Pirazinas/metabolismo
2.
Diabetes ; 73(3): 374-384, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37870907

RESUMO

Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, 6-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls, without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders.


Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Camundongos , Ratos , Humanos , Animais , Adiposidade , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/etiologia , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA