RESUMO
Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/uso terapêutico , Glucoquinase/metabolismo , Hipoglicemiantes/uso terapêutico , Pirrolidinas/uso terapêutico , Tiofenos/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/metabolismo , Ativadores de Enzimas/química , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/farmacologia , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacologiaRESUMO
In this paper, we report that a versatile method for the synthesis of 5'-selenium modified nucleosides has been explored on the basis of a 2-(trimethylsilyl)ethyl (TSE) selenyl group as a selenating donor. We demonstrate the broad utility of this method through direct introduction of various functional groups into 5'-TSE-selenonucleosides. This original method offers additional advantages for the preparation of these compounds, such as high functional group tolerance, ready availability of various electrophilic reagents, mild conditions, simple operation, and good yields. The utility of this approach is further demonstrated by the synthesis of Se-adenosyl-L-selenomethionine (SeAM) as a chemical reporter for methyltransferases.
Assuntos
Nucleosídeos/síntese química , Selênio/química , Selenometionina/síntese química , Metiltransferases/metabolismo , Estrutura Molecular , Nucleosídeos/química , Selenometionina/química , Selenometionina/metabolismoRESUMO
6-((2-Fluoro-3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propyl)amino)-2,3-dihydro-1H-inden-1-one is a potent drug-like G protein-coupled receptor 119 (GPR119) agonist. It is hoped that this compound would be instrumental in probing the pharmacological potential of GPR119 agonists.
Assuntos
Indenos/química , Indenos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Linhagem Celular , Teste de Tolerância a Glucose , Humanos , Indenos/síntese química , Indenos/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperidinas/síntese química , Piperidinas/farmacocinética , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/metabolismoRESUMO
We disclosed a novel series of G-protein coupled receptor 119 (GPR119) agonists based on a bicyclic amine scaffold. Through the optimization of hit compound 1, we discovered that the basic nitrogen atom of bicyclic amine played an important role in GPR119 agonist activity expression and that an indanone in various bicyclic rings was suitable in this series of compounds. The indanone derivative 2 showed the effect of plasma glucose control in oGTT and scGTT in the rodent model.
Assuntos
Aminas/química , Compostos Bicíclicos com Pontes/química , Hipoglicemiantes/síntese química , Indanos/síntese química , Pirimidinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Aminas/síntese química , Aminas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indanos/química , Indanos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
A safe and efficient process for the preparation of ethyl 2-methylthiophene-3-carboxylate (5) was devised. This process provides several advantages over the precedents, involving operational simplicity, avoidance of the use of strong bases such as n-butyllithium and application of noncryogenic conditions, and enabled to prepare 5 in 52% overall yield from commercially available 2-methylthiophene on a multikilogram scale.
Assuntos
Tiofenos/química , Tiofenos/síntese química , Compostos Organometálicos/químicaRESUMO
We investigated the superoxide anion scavenging effects of 2-amino-1,3- selenazoles and bis-(2-amino-5-selenazoyl) ketones using a highly sensitive quantitative chemiluminescence method. At 166 microM, the 2-amino-1,3-selenazoles and bis-(2-amino-5-selenazoyl) ketones scavenged in the range of 10.0 to 80.0% of O(2)(-). Bis[2-dimethylamino-5-(1,3-selenazolyl)] ketone exhibited the strongest superoxide anion-scavenging activity among the six kinds of 2-amino-1,3-selenazoles and three kinds of bis-(2-amino-5-selenazoyl) ketones. The 50% inhibitory concentration (IC(50)) of bis[2-dimethylamino-5-(1,3-selenazolyl)] ketone was determined to be 37.1 microM. Thus, bis[2-dimethylamino-5-(1,3-selenazolyl)] ketone acted in vitro as effective and potentially useful O(2)(-) scavenger.
