Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes

作者：Simon Szabo Laura; Kokas Marton; Greff Zoltan; Boros Sandor; Banhegyi Peter; Zsakai Lilian; Szantai Kis Csaba; Vantus Tibor; Mandl Jazsef; Banhegyi Gabor; Valyi Nagy Istvan; Orfi Laszlo; Ullrich Axel; Csala Miklos; Keri Gyorgy^*

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(2): 424-428.

DOI：10.1016/j.bmcl.2015.11.099

• Type 2 diabetes
• Lipotoxicity
• c-Jun N-terminal kinase
• IRS-1 phosphorylation
• Pyrido[2,3-d]pyrimidin

Activation of various interacting stress kinases, particularly the c-Jun N-terminal kinases (JNK), and a concomitant phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 play a central role both in insulin resistance and in beta-cell dysfunction. IRS-1 phosphorylation is stimulated by elevated free fatty acid levels through different pathways in obesity. A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity and type 2 diabetes.

• 出版日期2016-1-15