Ligand-Based Design, Synthesis, and Biological Evaluation of 2-Aminopyrimidines, a Novel Series of Receptor for Advanced Glycation End Products (RAGE) Inhibitors

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 A beta 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-A beta 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.