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

  • Bioorg Med Chem Lett. 2016 Jan 15;26(2):424-428. doi: 10.1016/j.bmcl.2015.11.099.
Laura Simon-Szabó  1 ,  Márton Kokas  1 ,  Zoltán Greff  2 ,  Sándor Boros  2 ,  Péter Bánhegyi  2 ,  Lilián Zsákai  2 ,  Csaba Szántai-Kis  2 ,  Tibor Vantus  3 ,  József Mandl  3 ,  Gábor Bánhegyi  4 ,  István Vályi-Nagy  5 ,  László Őrfi  6 ,  Axel Ullrich  7 ,  Miklós Csala  4 ,  György Kéri  8
Affiliations
  • 1. MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
  • 2. Vichem Chemie Research Ltd, 1022 Budapest, Hungary.
  • 3. MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary; Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
  • 4. Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary.
  • 5. United St. Istvan and St. Laszlo Hospital, 1097 Budapest, Hungary.
  • 6. Vichem Chemie Research Ltd, 1022 Budapest, Hungary; Department of Pharmaceutical Chemistry, Semmelweis University, 1092 Budapest, Hungary.
  • 7. Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany.
  • 8. MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1444 Budapest, Hungary; Vichem Chemie Research Ltd, 1022 Budapest, Hungary. Electronic address: [email protected].
PMID: 26704265 DOI: 10.1016/j.bmcl.2015.11.099
Abstract

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 β-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.

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