Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent
This article discloses the strategy that led to the discovery of a second series of hydroxyethylamine BACE-1 inhibitors with non-prime side substituents of higher binding efficiency. Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-07, Vol.19 (13), p.3669-3673 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Charrier, Nicolas Clarke, Brian Demont, Emmanuel Dingwall, Colin Dunsdon, Rachel Hawkins, Julie Hubbard, Julia Hussain, Ishrut Maile, Graham Matico, Rosalie Mosley, Julie Naylor, Alan O’Brien, Alistair Redshaw, Sally Rowland, Paul Soleil, Virginie Smith, Kathrine J. Sweitzer, Sharon Theobald, Pam Vesey, David Walter, Daryl S. Wayne, Gareth |
| description | This article discloses the strategy that led to the discovery of a second series of hydroxyethylamine BACE-1 inhibitors with non-prime side substituents of higher binding efficiency.
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors. |
| doi_str_mv | 10.1016/j.bmcl.2009.03.150 |
| format | Article |
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Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.03.150</identifier><identifier>PMID: 19477642</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; Alzheimer ; Alzheimer Disease - drug therapy ; Amyloid beta-Peptides - metabolism ; Animals ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; Aspartic Acid Endopeptidases - metabolism ; Aspartic protease ; BACE-1 ; Binding Sites ; Biological and medical sciences ; Computer Simulation ; Crystallography, X-Ray ; Ethylamines - chemical synthesis ; Ethylamines - chemistry ; Ethylamines - pharmacology ; Humans ; Hydroxyethylamine ; Medical sciences ; Mice ; Neuropharmacology ; Pharmacology. Drug treatments ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Rats ; Structure-Activity Relationship ; Thiazines - chemistry ; Thiazines - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-07, Vol.19 (13), p.3669-3673</ispartof><rights>2009 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-ac53923088ae5c917dc5aa48a1f6450cd84ed63bda90dd4421e2dea0c27bde193</citedby><cites>FETCH-LOGICAL-c384t-ac53923088ae5c917dc5aa48a1f6450cd84ed63bda90dd4421e2dea0c27bde193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2009.03.150$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21650148$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19477642$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Charrier, Nicolas</creatorcontrib><creatorcontrib>Clarke, Brian</creatorcontrib><creatorcontrib>Demont, Emmanuel</creatorcontrib><creatorcontrib>Dingwall, Colin</creatorcontrib><creatorcontrib>Dunsdon, Rachel</creatorcontrib><creatorcontrib>Hawkins, Julie</creatorcontrib><creatorcontrib>Hubbard, Julia</creatorcontrib><creatorcontrib>Hussain, Ishrut</creatorcontrib><creatorcontrib>Maile, Graham</creatorcontrib><creatorcontrib>Matico, Rosalie</creatorcontrib><creatorcontrib>Mosley, Julie</creatorcontrib><creatorcontrib>Naylor, Alan</creatorcontrib><creatorcontrib>O’Brien, Alistair</creatorcontrib><creatorcontrib>Redshaw, Sally</creatorcontrib><creatorcontrib>Rowland, Paul</creatorcontrib><creatorcontrib>Soleil, Virginie</creatorcontrib><creatorcontrib>Smith, Kathrine J.</creatorcontrib><creatorcontrib>Sweitzer, Sharon</creatorcontrib><creatorcontrib>Theobald, Pam</creatorcontrib><creatorcontrib>Vesey, David</creatorcontrib><creatorcontrib>Walter, Daryl S.</creatorcontrib><creatorcontrib>Wayne, Gareth</creatorcontrib><title>Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>This article discloses the strategy that led to the discovery of a second series of hydroxyethylamine BACE-1 inhibitors with non-prime side substituents of higher binding efficiency.
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.</description><subject>Administration, Oral</subject><subject>Alzheimer</subject><subject>Alzheimer Disease - drug therapy</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>Aspartic Acid Endopeptidases - metabolism</subject><subject>Aspartic protease</subject><subject>BACE-1</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray</subject><subject>Ethylamines - chemical synthesis</subject><subject>Ethylamines - chemistry</subject><subject>Ethylamines - pharmacology</subject><subject>Humans</subject><subject>Hydroxyethylamine</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. 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Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19477642</pmid><doi>10.1016/j.bmcl.2009.03.150</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2009-07, Vol.19 (13), p.3669-3673 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Administration, Oral Alzheimer Alzheimer Disease - drug therapy Amyloid beta-Peptides - metabolism Animals Aspartic Acid Endopeptidases - antagonists & inhibitors Aspartic Acid Endopeptidases - metabolism Aspartic protease BACE-1 Binding Sites Biological and medical sciences Computer Simulation Crystallography, X-Ray Ethylamines - chemical synthesis Ethylamines - chemistry Ethylamines - pharmacology Humans Hydroxyethylamine Medical sciences Mice Neuropharmacology Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Structure-Activity Relationship Thiazines - chemistry Thiazines - pharmacology |
| title | Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent |
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