title: Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors.
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.
authors: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
authors: Young Taek
authors: YT
authors: Han
authors: Gyeong-In
authors: GI
authors: Choi
authors: Dohyun
authors: D
authors: Son
authors: Nam-Jung
authors: NJ
authors: Kim
authors: Hwayoung
authors: H
authors: Yun
authors: Sujin
authors: S
authors: Lee
authors: Dong Jo
authors: DJ
authors: Chang
authors: Hyun-Seok
authors: HS
authors: Hong
authors: Hee
authors: H
authors: Kim
authors: Hee-Jin
authors: HJ
authors: Ha
authors: Young-Ho
authors: YH
authors: Kim
authors: Hyun-Ju
authors: HJ
authors: Park
authors: Jeewoo
authors: J
authors: Lee
authors: Young-Ger
authors: YG
authors: Suh
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C578480:4,6-bis(4-chlorophenyl)-N-(3-(2-(diethylamino)ethoxy)phenyl)pyrimidin-2-amine; D016229:Amyloid beta-Peptides; D005021:Ethylamines; D017127:Glycation End Products, Advanced; D008024:Ligands; D011743:Pyrimidines