Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase

Lei Zhang, Xiaojie Chen, Jun Liu, Qingzhang Zhu, Ying Leng, Xiaomin Luo, Hualiang Jiang, Hong Liu

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Dual-target-directed agents simultaneously inhibiting glycogen phosphorylase (GP) and activating glucokinase (GK) could decelerate the inflow of glucose from glycogenolysis and accelerate the outflow of glucose in the liver, therefore allow for a better control over hyperglycaemia in a synergetic manner. A series of hybrid compounds were designed by structure-assisted and ligand-based strategies. In vitro bioassays found two novel compounds (1j, 6g) worthy of further optimization on balance of dual action to GP and GK. In addition, for single-target activity, two compounds exhibited more potent GP inhibitory activity and four compounds showed better GK activation than their corresponding references.

Original languageEnglish (US)
Pages (from-to)624-639
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume58
DOIs
StatePublished - Dec 2012
Externally publishedYes

Keywords

  • Dual-target-directed
  • Glucokinase activators
  • Glycogen phosphorylase inhibitors
  • Hybrid
  • Type 2 diabetes

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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