Abstract
Using the approach of ligand-based drug design, we discovered a novel series of 4,6-disubstituted 2-aminopyrimidines as RAGE inhibitors. In transgenic mouse models of AD, one of the 4,6-bis(4-chlorophenyl)pyrimidine analogs, 59, significantly lowered the concentration of toxic soluble Aβ in the brain and improved cognitive function. SPR analysis confirmed the direct binding of 59 with RAGE, which should contribute to its biological activities via inhibition of the RAGE-Aβ interaction. We also predicted the binding mode of the 4,6-bis(4-chlorophenyl)pyrimidine analogs to the RAGE V-domain through flexible docking study.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alzheimer Disease / drug therapy
-
Alzheimer Disease / metabolism
-
Alzheimer Disease / psychology
-
Amyloid beta-Peptides / genetics
-
Amyloid beta-Peptides / metabolism
-
Animals
-
Brain / metabolism
-
Cell Line, Tumor
-
Drug Design
-
Ethylamines / chemical synthesis*
-
Ethylamines / pharmacokinetics
-
Ethylamines / pharmacology
-
Glycation End Products, Advanced / antagonists & inhibitors*
-
Humans
-
Ligands
-
Male
-
Maze Learning / drug effects
-
Mice
-
Mice, Inbred ICR
-
Mice, Transgenic
-
Molecular Conformation
-
Molecular Docking Simulation
-
Protein Binding
-
Pyrimidines / chemical synthesis*
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Structure-Activity Relationship
Substances
-
4,6-bis(4-chlorophenyl)-N-(3-(2-(diethylamino)ethoxy)phenyl)pyrimidin-2-amine
-
Amyloid beta-Peptides
-
Ethylamines
-
Glycation End Products, Advanced
-
Ligands
-
Pyrimidines