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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2010-4-30
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pubmed:abstractText |
We previously reported potent BACE1 inhibitors KMI-420 and KMI-570 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Acidic moieties at the P(1)(') and P(4) positions of KMI inhibitors are thought to be unfavorable in terms of membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P(4) position with hydrogen bond accepting groups and acidic moieties at the P(1)(') position with less acidic and similar molecular-size moieties (carboxylic acid or tetrazole bioisosteres). These inhibitors exhibited improved BACE1 inhibitory activities and a thorough quantitative structure-activity relationship study was performed.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1464-3391
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pubmed:author |
pubmed-author:Abdel-RahmanHamdyH,
pubmed-author:HamadaTakashiT,
pubmed-author:HamadaYoshioY,
pubmed-author:HidakaKoushiK,
pubmed-author:IgawaNaotoN,
pubmed-author:IkariHayatoH,
pubmed-author:KimuraTooruT,
pubmed-author:KisoYoshiakiY,
pubmed-author:NagamineAyakaA,
pubmed-author:NguyenJeffrey-TriJT,
pubmed-author:SohmaYouheiY,
pubmed-author:TagadHarichandra DHD,
pubmed-author:YamaniAbdellahA
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pubmed:copyrightInfo |
(c) 2010 Elsevier Ltd. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
18
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3175-86
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pubmed:meshHeading |
pubmed-meshheading:20381362-Amyloid Precursor Protein Secretases,
pubmed-meshheading:20381362-Aspartic Acid Endopeptidases,
pubmed-meshheading:20381362-Carboxylic Acids,
pubmed-meshheading:20381362-Crystallography, X-Ray,
pubmed-meshheading:20381362-Drug Design,
pubmed-meshheading:20381362-Enzyme Inhibitors,
pubmed-meshheading:20381362-Humans,
pubmed-meshheading:20381362-Hydrogen Bonding,
pubmed-meshheading:20381362-Hydrogen-Ion Concentration,
pubmed-meshheading:20381362-Inhibitory Concentration 50,
pubmed-meshheading:20381362-Models, Molecular,
pubmed-meshheading:20381362-Molecular Structure,
pubmed-meshheading:20381362-Oligopeptides,
pubmed-meshheading:20381362-Thiazoles,
pubmed-meshheading:20381362-Triazoles
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pubmed:year |
2010
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pubmed:articleTitle |
Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P1' and P4 positions.
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pubmed:affiliation |
Department of Medicinal Chemistry, Centre Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto 607-8412, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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