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| [[Image:2fdp.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2fdp| PDB=2fdp | SCENE= }} | | {{STRUCTURE_2fdp| PDB=2fdp | SCENE= }} |
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| '''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''
| | ===Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16451048}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16451048 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16451048}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Aspartyl protease]] | | [[Category: Aspartyl protease]] |
| [[Category: Bace]] | | [[Category: Bace]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 03:46:24 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 00:59:11 2008'' |
