| Fluorinated piperidine acetic acids as gamma-secretase modulators. | |
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MedLine Citation:
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PMID: 20005099 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects. |
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Authors:
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Matthew G Stanton; Jed Hubbs; David Sloman; Christopher Hamblett; Paula Andrade; Minilik Angagaw; Grace Bi; Regina M Black; Jamie Crispino; Jonathan C Cruz; Eric Fan; Georgia Farris; Bethany L Hughes; Candia M Kenific; Richard E Middleton; George Nikov; Peter Sajonz; Sanjiv Shah; Nirah Shomer; Alexander A Szewczak; Flobert Tanga; Matthew T Tudge; Mark Shearman; Benito Munoz |
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Publication Detail:
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Type: Journal Article Date: 2009-11-13 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 20 ISSN: 1464-3405 ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-02-03 Completed Date: 2010-04-20 Revised Date: - |
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: 755-8 Citation Subset: IM |
Copyright Information:
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Copyright 2009 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. matthew_stanton@merck.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetic Acids
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chemical synthesis,
chemistry*,
pharmacokinetics Amyloid Precursor Protein Secretases / metabolism* Amyloid beta-Protein / genetics, metabolism Animals Diazonium Compounds / chemistry Disease Models, Animal Fluorine / chemistry* Mice Mice, Transgenic Peptide Fragments / genetics, metabolism Piperidines / chemical synthesis, chemistry*, pharmacokinetics Rats Receptors, Notch / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Acetic Acids; 0/Amyloid beta-Protein; 0/Diazonium Compounds; 0/Peptide Fragments; 0/Piperidines; 0/Receptors, Notch; 0/amyloid beta-protein (1-42); 0/selectfluor; 7782-41-4/Fluorine; EC 3.4.-/Amyloid Precursor Protein Secretases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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