RESUMO
The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose-lowering effect in diabetic rats.
Assuntos
Hipoglicemiantes/química , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Animais , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Ratos , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/química , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be useful in treating either advanced or recurrent KRAS/NRAS/BRAF wild-type colorectal cancer. We herein report the case of a 60-year-old man with short bowel syndrome who developed hematochezia due to panitumumab-induced colitis with vitamin K deficiency during third-line chemotherapy. The cause of vitamin K deficiency was the lack of intravenous vitamin K supplementation following a change from central venous nutrition to peripheral venous nutrition. We advise clinicians to carefully check for colitis and manage the infusions of chemotherapy patients with short bowel syndrome.