Document Detail

Dual-target-directed 1,3-diphenylurea derivatives: BACE 1 inhibitor and metal chelator against Alzheimer's disease.
MedLine Citation:
PMID:  20620068     Owner:  NLM     Status:  MEDLINE    
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.
Wenhai Huang; Dan Lv; Haiping Yu; Rong Sheng; Sun Chol Kim; Peng Wu; Kedi Luo; Jia Li; Yongzhou Hu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-17
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  18     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-23     Completed Date:  2010-11-02     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  5610-5     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Zijingang Campus, Hangzhou 310058, China.
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MeSH Terms
Alzheimer Disease / drug therapy
Amyloid Precursor Protein Secretases / antagonists & inhibitors*,  metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*,  metabolism
Binding Sites
Butyrates / chemistry,  therapeutic use
Carbanilides / chemical synthesis,  chemistry*,  therapeutic use
Chelating Agents / chemistry*,  therapeutic use
Computer Simulation
Metals / chemistry
Models, Molecular
Phenylurea Compounds / chemical synthesis,  chemistry*,  therapeutic use
Reg. No./Substance:
0/1-(2-(2-(6-aminohexylamino)ethoxy)-5-bromophenyl)-3-(2-chlorophenyl)urea; 0/Butyrates; 0/Carbanilides; 0/Chelating Agents; 0/LR-90; 0/Metals; 0/Phenylurea Compounds; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC protein, human

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