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. Epub 2015 Nov 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacology*
  • Insulin Receptor Substrate Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Serine / metabolism*

Substances

  • Hypoglycemic Agents
  • Insulin Receptor Substrate Proteins
  • Pyrimidines
  • Serine
  • JNK Mitogen-Activated Protein Kinases