title: 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.
authors.affiliation: College of Pharmacy, Woosuk University, Wanju 565-701, Republic of Korea.
authors.forename: Young Taek
authors.initials: YT
authors.lastname: Han
authors.affiliation: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Kyeojin
authors.initials: K
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Dohyun
authors.initials: D
authors.lastname: Son
authors.affiliation: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Hongchan
authors.initials: H
authors.lastname: An
authors.affiliation: Medifron DBT, Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 425-839, Republic of Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea. Electronic address: ygsuh@snu.ac.kr.
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
mesh_terms: D018360:Crystallography, X-Ray; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013329:Structure-Activity Relationship
chemical_list: D011743:Pyrimidines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: 2-(N,N-Diethylamino)ethoxy moiety; 2-Aminopyrimidine; RAGE inhibitor; Receptor for advanced glycation end products; Structure–activity relationship