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rdf:type |
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lifeskim:mentions |
umls-concept:C0002483,
umls-concept:C0013682,
umls-concept:C0023175,
umls-concept:C0023688,
umls-concept:C0079411,
umls-concept:C0178539,
umls-concept:C0185125,
umls-concept:C0205314,
umls-concept:C0243077,
umls-concept:C0439282,
umls-concept:C0439596,
umls-concept:C0441655,
umls-concept:C0679622,
umls-concept:C1454853,
umls-concept:C1880355
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pubmed:issue |
24
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pubmed:dateCreated |
2007-11-26
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pubmed:databankReference |
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pubmed:abstractText |
Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.
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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 |
Nov
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AharonyDavidD,
pubmed-author:AlbertJeffrey SJS,
pubmed-author:AndisikDonaldD,
pubmed-author:CallaghanOwenO,
pubmed-author:CampbellJames BJB,
pubmed-author:CarrRobin ARA,
pubmed-author:ChessariGianniG,
pubmed-author:CongreveMilesM,
pubmed-author:EdwardsPhilip DPD,
pubmed-author:FolmerRutger H ARH,
pubmed-author:FredericksonMartynM,
pubmed-author:GeschwindnerStefanS,
pubmed-author:KoetherGerardG,
pubmed-author:KolmodinKarinK,
pubmed-author:KrumrineJenniferJ,
pubmed-author:MaugerRussell CRC,
pubmed-author:MurrayChristopher WCW,
pubmed-author:OlssonLise-LotteLL,
pubmed-author:PatelSahilS,
pubmed-author:SpearNateN,
pubmed-author:SylvesterMarkM,
pubmed-author:TianGaochaoG
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pubmed:issnType |
Print
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pubmed:day |
29
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5912-25
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:17985862-Amidines,
pubmed-meshheading:17985862-Amyloid Precursor Protein Secretases,
pubmed-meshheading:17985862-Aspartic Acid Endopeptidases,
pubmed-meshheading:17985862-Cell Line,
pubmed-meshheading:17985862-Crystallography, X-Ray,
pubmed-meshheading:17985862-Cytosine,
pubmed-meshheading:17985862-Fluorescence Resonance Energy Transfer,
pubmed-meshheading:17985862-Humans,
pubmed-meshheading:17985862-Ligands,
pubmed-meshheading:17985862-Magnetic Resonance Spectroscopy,
pubmed-meshheading:17985862-Models, Molecular,
pubmed-meshheading:17985862-Pyrimidines,
pubmed-meshheading:17985862-Stereoisomerism,
pubmed-meshheading:17985862-Structure-Activity Relationship
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pubmed:year |
2007
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pubmed:articleTitle |
Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.
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pubmed:affiliation |
CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19850-5437, USA. philip.edwards@astrazeneca.com
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pubmed:publicationType |
Journal Article
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