Fine tuning of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine focusing on the activity-sensitive aminoalkoxy moiety for a therapeutically useful inhibitor of receptor for advanced glycation end products (RAGE)

Abstract

Through the fine tuning of the activity-sensitive aminoalkoxy moiety of 4,6-bisphenyl-2-(3-alkoxyanilino)pyrimidine as a novel inhibitor of the receptor for advanced glycation end products (RAGE), the tertiary amine was elucidated as an essential part associated with RAGE inhibition. On the basis of this finding, a 3-(N,N-dimethylamino)pyrrolidine analog 12o was identified as a therapeutically useful RAGE inhibitor with improved activity and solubility. Molecular modeling studies predicted that the improved inhibitory activity is induced by additional hydrogen bonds between the nitrogen atom of the pyrrolidine ring and Arg48 and by an interaction between the dimethylamino-substituent of the pyrrolidine moiety and a relatively hydrophobic groove in the RAGE binding site. (C) 2014 Elsevier Ltd. All rights reserved.