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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2006-2-2
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pubmed:databankReference |
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pubmed:abstractText |
A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.
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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 |
Feb
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BallingerMarcus DMD,
pubmed-author:FuciniRaymond VRV,
pubmed-author:GordonEric MEM,
pubmed-author:HuntSS,
pubmed-author:JacobsJeffrey WJW,
pubmed-author:LamMelissaM,
pubmed-author:LuYafanY,
pubmed-author:McDowellRobert SRS,
pubmed-author:RandalMikeM,
pubmed-author:ShiXiao-PingXP,
pubmed-author:ThomasAnila EAE,
pubmed-author:WalchOO,
pubmed-author:WilkinsonJennifer MJM,
pubmed-author:YangWenjinW,
pubmed-author:ZhongMinM
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pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
839-42
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16451048-Amyloid Precursor Protein Secretases,
pubmed-meshheading:16451048-Aspartic Acid Endopeptidases,
pubmed-meshheading:16451048-Binding Sites,
pubmed-meshheading:16451048-Cell Line,
pubmed-meshheading:16451048-Crystallography, X-Ray,
pubmed-meshheading:16451048-Dipeptides,
pubmed-meshheading:16451048-Endopeptidases,
pubmed-meshheading:16451048-Ethylamines,
pubmed-meshheading:16451048-Humans,
pubmed-meshheading:16451048-Models, Molecular,
pubmed-meshheading:16451048-Molecular Structure,
pubmed-meshheading:16451048-Protease Inhibitors,
pubmed-meshheading:16451048-Structure-Activity Relationship
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pubmed:year |
2006
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pubmed:articleTitle |
Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1.
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pubmed:affiliation |
Departments of Chemistry, Biochemistry, and Structural Biology, Sunesis Pharmaceuticals Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. wenjin@sunesis.com
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, N.I.H., Extramural
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