| BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. | |
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MedLine Citation:
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PMID: 18171615 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays. |
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Authors:
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Paul Beswick; Nicolas Charrier; Brian Clarke; Emmanuel Demont; Colin Dingwall; Rachel Dunsdon; Andrew Faller; Robert Gleave; Julie Hawkins; Ishrut Hussain; Christopher N Johnson; David MacPherson; Graham Maile; Rosalie Matico; Peter Milner; Julie Mosley; Alan Naylor; Alistair O'Brien; Sally Redshaw; David Riddell; Paul Rowland; John Skidmore; Virginie Soleil; Kathrine J Smith; Steven Stanway; Geoffrey Stemp; Alistair Stuart; Sharon Sweitzer; Pam Theobald; David Vesey; Daryl S Walter; John Ward; Gareth Wayne |
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Publication Detail:
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Type: Journal Article Date: 2007-12-15 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 18 ISSN: 1464-3405 ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2008 Feb |
Date Detail:
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Created Date: 2008-02-05 Completed Date: 2008-03-24 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 1022-6 Citation Subset: IM |
Affiliation:
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Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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drug therapy,
metabolism* Amyloid beta-Protein Precursor / antagonists & inhibitors Animals Asparagine / chemistry Aspartic Acid Endopeptidases / antagonists & inhibitors* Combinatorial Chemistry Techniques* Crystallography, X-Ray Disease Models, Animal Ethylamines / chemical synthesis*, chemistry, pharmacology* Fluorine / chemistry Mice Molecular Structure Nanotechnology Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Amyloid beta-Protein Precursor; 0/Ethylamines; 7006-34-0/Asparagine; 75-04-7/ethylamine; 7782-41-4/Fluorine; EC 3.4.23.-/Aspartic Acid Endopeptidases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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