Synthesis and structure-activity relationships of tri-substituted thiazoles as RAGE antagonists for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7555-61. doi: 10.1016/j.bmcl.2012.10.022. Epub 2012 Oct 13.

Abstract

A series of thiazole derivatives were designed, and prepared to develop RAGE antagonist for the treatment of Alzheimer's disease (AD). SAR studies were performed to optimize inhibitory activity on Aβ-RAGE binding. SAR studies showed that introducing an amino group at part A was essential for inhibitory activity on Aβ-RAGE binding. Compounds selected from Aβ-RAGE binding screening displayed inhibitory activity on Aβ transport across BBB. They also showed inhibitory activity against Aβ-induced NF-κB activation. These results indicated that our derivatives had a potential as therapeutic agent for the treatment of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Thiazoles