Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors
This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micro...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (7), p.1942-1947 |
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| container_end_page | 1947 |
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| container_issue | 7 |
| container_start_page | 1942 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 21 |
| creator | Rueeger, Heinrich Rondeau, Jean-Michel McCarthy, Clive Möbitz, Henrik Tintelnot-Blomley, Marina Neumann, Ulf Desrayaud, Sandrine |
| description | This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described. |
| doi_str_mv | 10.1016/j.bmcl.2011.02.038 |
| format | Article |
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The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.02.038</identifier><identifier>PMID: 21388807</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Alzheimer’s disease ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; BACE-1 ; Benzylamines - chemical synthesis ; Benzylamines - chemistry ; Benzylamines - pharmacology ; Biological and medical sciences ; brain ; chemistry ; Crystallography, X-Ray ; Cyclic S-Oxides - chemical synthesis ; Cyclic S-Oxides - chemistry ; Cyclic S-Oxides - pharmacology ; Cyclization ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; HEA ; Hydroxyethylamine transition state mimetic ; Medical sciences ; Models, Molecular ; Molecular Structure ; Neuropharmacology ; Pharmacology. Drug treatments ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Structure-Activity Relationship ; X-radiation ; β-Secretase inhibitor</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-04, Vol.21 (7), p.1942-1947</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c507t-1606f0d67a80678b7dde40d4dae8afa18b71025c5924bbd48c900673e97acc7c3</citedby><cites>FETCH-LOGICAL-c507t-1606f0d67a80678b7dde40d4dae8afa18b71025c5924bbd48c900673e97acc7c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11002228$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23982111$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21388807$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rueeger, Heinrich</creatorcontrib><creatorcontrib>Rondeau, Jean-Michel</creatorcontrib><creatorcontrib>McCarthy, Clive</creatorcontrib><creatorcontrib>Möbitz, Henrik</creatorcontrib><creatorcontrib>Tintelnot-Blomley, Marina</creatorcontrib><creatorcontrib>Neumann, Ulf</creatorcontrib><creatorcontrib>Desrayaud, Sandrine</creatorcontrib><title>Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.</description><subject>Alzheimer’s disease</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>BACE-1</subject><subject>Benzylamines - chemical synthesis</subject><subject>Benzylamines - chemistry</subject><subject>Benzylamines - pharmacology</subject><subject>Biological and medical sciences</subject><subject>brain</subject><subject>chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Cyclic S-Oxides - chemical synthesis</subject><subject>Cyclic S-Oxides - chemistry</subject><subject>Cyclic S-Oxides - pharmacology</subject><subject>Cyclization</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HEA</subject><subject>Hydroxyethylamine transition state mimetic</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</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. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Structure-Activity Relationship</subject><subject>X-radiation</subject><subject>β-Secretase inhibitor</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0VGL1DAQB_AgireefgEfNC-igq2TNE1T8GVvWT3hQHA98EVCmkxvs3Tbu6Q97Lc3y676pk8J4TeT4T-EPGeQM2Dy_S5v9rbLOTCWA8-hUA_IggkpskJA-ZAsoJaQqVp8PyNPYtwBMAFCPCZnnBVKKagW5MdmDJMdp4C0MREddRj9Tf-Oxrkft-keqekd3Sy_0qGldradt3Q7uzD8nHHczp3Z-x7pm8v18i29WK7WGaO-3_rGj0OIT8mj1nQRn53Oc3L9cf1tdZldffn0ebW8ymwJ1ZgxCbIFJyujQFaqqZxDAU44g8q0hqUXBry0Zc1F0zihbA0JFlhXxtrKFufk9bHvbRjuJoyj3vtosetMj8MUtZK8UgIU-78sK1YA8CJJfpQ2DDEGbPVt8HsTZs1AH_LXO33IXx_y18B1yj8VvTi1n5o9uj8lvwNP4NUJmGhN1wbTWx__uqJWnLHDnC-PrjWDNjchmetN-qlMSyyEZDKJD0eBKdh7j0FH67G36HxAO2o3-H9N-gsISasf</recordid><startdate>20110401</startdate><enddate>20110401</enddate><creator>Rueeger, Heinrich</creator><creator>Rondeau, Jean-Michel</creator><creator>McCarthy, Clive</creator><creator>Möbitz, Henrik</creator><creator>Tintelnot-Blomley, Marina</creator><creator>Neumann, Ulf</creator><creator>Desrayaud, Sandrine</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20110401</creationdate><title>Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors</title><author>Rueeger, Heinrich ; Rondeau, Jean-Michel ; McCarthy, Clive ; Möbitz, Henrik ; Tintelnot-Blomley, Marina ; Neumann, Ulf ; Desrayaud, Sandrine</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c507t-1606f0d67a80678b7dde40d4dae8afa18b71025c5924bbd48c900673e97acc7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Alzheimer’s disease</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>BACE-1</topic><topic>Benzylamines - chemical synthesis</topic><topic>Benzylamines - chemistry</topic><topic>Benzylamines - pharmacology</topic><topic>Biological and medical sciences</topic><topic>brain</topic><topic>chemistry</topic><topic>Crystallography, X-Ray</topic><topic>Cyclic S-Oxides - chemical synthesis</topic><topic>Cyclic S-Oxides - chemistry</topic><topic>Cyclic S-Oxides - pharmacology</topic><topic>Cyclization</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>HEA</topic><topic>Hydroxyethylamine transition state mimetic</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. 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| subjects | Alzheimer’s disease Amyloid Precursor Protein Secretases - antagonists & inhibitors Aspartic Acid Endopeptidases - antagonists & inhibitors BACE-1 Benzylamines - chemical synthesis Benzylamines - chemistry Benzylamines - pharmacology Biological and medical sciences brain chemistry Crystallography, X-Ray Cyclic S-Oxides - chemical synthesis Cyclic S-Oxides - chemistry Cyclic S-Oxides - pharmacology Cyclization Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology HEA Hydroxyethylamine transition state mimetic Medical sciences Models, Molecular Molecular Structure Neuropharmacology Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Structure-Activity Relationship X-radiation β-Secretase inhibitor |
| title | Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors |
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