Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease

Bioorg Med Chem Lett. 2023 Oct 1:94:129461. doi: 10.1016/j.bmcl.2023.129461. Epub 2023 Aug 29.

Abstract

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

Keywords: Fatty liver; Obesity; TPH inhibitor; Xanthine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids*
  • Diuretics
  • Humans
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Obesity / drug therapy
  • Tryptophan Hydroxylase / antagonists & inhibitors
  • Xanthines / chemistry
  • Xanthines / pharmacology

Substances

  • Alkaloids
  • Diuretics
  • TPH1 protein, human
  • Tryptophan Hydroxylase
  • Xanthines