RESUMO
Pazopanib (trade name Votrient®) is a potent and selective multi-targeted tyrosine kinase inhibitor that blocks tumor growth and inhibits angiogenesis. Based on a recently reported procedure, we herein report the first synthesis of four potential process impurities generated in the production of pazopanib. The structure of these impurities were synthesized and characterized by 1H NMR, 13C NMR and HRMS data. The possible formation mechanisms of these impurities were also elucidated. These findings should be useful for the quality control of pazopanib in manufacture.
Assuntos
Inibidores da Angiogênese/química , Contaminação de Medicamentos , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Sulfonamidas/química , Indazóis , Espectroscopia de Ressonância Magnética/métodos , Controle de QualidadeRESUMO
2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (IV), a key intermediate of saxagliptin for type 2 diabetes mellitus (T2DM), was prepared from 1-adamantanecarboxylic acid(I) via oxidation by potassium permanganate(KMnO4) to afford 3-hydroxy-1-adamantanecarboxylic acid (II), which was treated with a one-pot method to give 1-acetyl-3-hydroxyadamantane (III) followed by oxidation. Some key steps were optimized and the overall yield was about 51%.
Assuntos
Acetatos/síntese química , Adamantano/análogos & derivados , Adamantano/síntese química , Técnicas de Química Sintética/métodos , Dipeptídeos/química , Hipoglicemiantes/síntese química , Acetatos/química , Acetatos/farmacologia , Adamantano/química , Adamantano/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Estrutura Molecular , Permanganato de Potássio/químicaRESUMO
Pioglitazone/metformin adduct is a novel compound synthesized from pioglitazone and metformin combined at a molar mass ratio of 1:1. The aim of this study was to investigate the effects of pioglitazone/metformin adduct on high glucose-induced insulin secretion and apoptosis in INS-1 cells. Western blot and CCK8 analyses showed that the death rate of INS-1 cells increased in response to glucose treatment in a concentration-dependent manner. ELISA assays and Western blot analyses showed that insulin secretion peaked following treatment with glucose concentration at 33.33 mM. Treatment of INS-1 cells with 1 µM pioglitazone/metformin adduct in the presence of 33.33 mM glucose greatly improveded the levels of insulin and apoptosis rates compared to those of the control group. Analysis of mechanism underlying these effects revealed the involvement of the p21-p53-MDM2 signaling pathway. Our results indicate that pioglitazone/metformin adduct is superior to pioglitazone and/or metformin in regulating high glucose-induced insulin secretion and apoptosis in INS-1 cells.
Assuntos
Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Metformina/farmacologia , Pioglitazona/farmacologia , Animais , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Sinergismo Farmacológico , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Ratos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The aim of this study was to prepare the rosiglitazone sodium enteric-coated tablets and investigate its release rate. The rosiglitazone sodium enteric-coated tablet was prepared by single punch tablet press using substituted hydroxypropyl cellulose and polyvinylpyrrolidone (PVP). The release rate from the enteric-coated tablet of rosiglitazone sodium was evaluated. The release rate study showed that few rosiglitazone sodium was released from enteric coated formulation within 2 h in simulated gastric juice, while it released more than 80% of the labeled amount in 30 min in simulated intestinal juice. The preparing method of rosiglitazone sodium enteric-coated tablets was simple and had a good reproducibility. The release condition and determined methods could be used for the routine determinations of rosiglitazone sodium enteric-coated tablets.