Lipid accumulation inhibitory activities of novel isoxazole-based chenodeoxycholic acids: Design, synthesis and preliminary mechanism study

Bioorg Med Chem Lett. 2018 Sep 15;28(17):2879-2884. doi: 10.1016/j.bmcl.2018.07.026. Epub 2018 Jul 17.

Abstract

In continuation of our drug discovery program on hyperlipidemia, a series of novel isoxazole-chenodeoxycholic acid hybrids were designed, synthesized and evaluated for their lipid-lowering effects. Preliminary screening of all the synthesized compounds was done by using a 3T3-L1 adipocyte model, in which the most active compound 16b could significantly reduce the lipid accumulation up to 30.5% at a nontoxic concentration 10 μM. Further mechanism studies revealed that 16b blocked lipid accumulation via activating FXR-SHP signaling pathway, efficiently down-regulated the expression of key lipogenesis regulator SREBP-1c.

Keywords: 3T3-L1 adipocytes; FXR; Hybrids; Hyperlipidemia; SREBP-1c.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Animals
  • Cell Survival / drug effects
  • Chenodeoxycholic Acid / chemical synthesis
  • Chenodeoxycholic Acid / chemistry
  • Chenodeoxycholic Acid / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Hep G2 Cells
  • Humans
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Lipids / antagonists & inhibitors*
  • Lipids / biosynthesis
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Isoxazoles
  • Lipids
  • Chenodeoxycholic Acid