title: Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer's disease.
abstract: Dual-target-directed 1,3-diphenylurea derivatives were designed by hybridizing BACE 1 inhibitor 1 with metal chelator LR-90. A database consisted of 1,3-diphenylurea derivatives was built and screened by the pharmacophore model (Hypo 1) of BACE 1 inhibitor. Based on the predicted results, 11 compounds (6a-d, 9a-g) with favorable Fitvalues were selected, synthesized and evaluated for their BACE 1 inhibitory activities, which showed that the predicted results were in good agreement with the experimental values. Besides, the synthesized compounds also displayed the ability to chelate metal ions. The most effective BACE 1 inhibitor 9f (27.85+/-2.46 micromol/L) was selected for further receptor-binding studies, the result of which indicated that an essential hydrogen bonds was formed between the urea group of 9f and the catalytic aspartate Asp228.
authors.affiliation: ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Zijingang Campus, Hangzhou 310058, China.
authors.forename: Wenhai
authors.initials: W
authors.lastname: Huang
authors.forename: Dan
authors.initials: D
authors.lastname: Lv
authors.forename: Haiping
authors.initials: H
authors.lastname: Yu
authors.forename: Rong
authors.initials: R
authors.lastname: Sheng
authors.forename: Sun Chol
authors.initials: SC
authors.lastname: Kim
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Kedi
authors.initials: K
authors.lastname: Luo
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002087:Butyrates / Q000737:chemistry / Q000627:therapeutic use; D002224:Carbanilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D002614:Chelating Agents / Q000737:chemistry* / Q000627:therapeutic use; D003198:Computer Simulation; D006801:Humans; D008670:Metals / Q000737:chemistry; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: C553151:1-(2-(2-(6-aminohexylamino)ethoxy)-5-bromophenyl)-3-(2-chlorophenyl)urea; D002087:Butyrates; D002224:Carbanilides; D002614:Chelating Agents; C485003:LR-90; D008670:Metals; D010671:Phenylurea Compounds; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human