Synthesis, in vitro and in silico studies of a PPARγ and GLUT-4 modulator with hypoglycemic effect

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4575-4579. doi: 10.1016/j.bmcl.2014.07.068. Epub 2014 Aug 1.

Abstract

Compound {4-[({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetyl)amino]phenoxy}acetic acid (1) was prepared and the in vitro relative expression of PPARγ, GLUT-4 and PPARα, was estimated. Compound 1 showed an increase of 2-fold in the mRNA expression of PPARγ isoform, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/Kg single dose using a non insulin dependent diabetes mellitus (NIDDM) rat model. The in vivo results indicated a significant decrease of plasma glucose levels, during the 7 h post-administration. Also, we performed a molecular docking of compound 1 into the ligand binding pocket of PPARγ, showing important short contacts with residues Ser289, His323 and His449 in the active site.

Keywords: Diabetes; Molecular docking; PPAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Disease Models, Animal
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism*
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use*
  • Ligands
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Thiazolidines / chemistry
  • Thiazolidines / pharmacology*
  • Thiazolidines / therapeutic use*

Substances

  • 4-(((4-((Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl)phenoxy)acetyl)amino)phenoxy)acetic acid
  • Glucose Transporter Type 4
  • Hypoglycemic Agents
  • Ligands
  • PPAR gamma
  • RNA, Messenger
  • Thiazolidines