Design of potent inhibitors of human β-secretase. Part 2
We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of β-secretase that incorporate a variety of P 2 side chains that yield potent inhibitors with excellent cellular activity and good selectivity against Cathepsin-D. We describe an optimized series of acyclic hydr...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007, Vol.17 (1), p.78-81 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Freskos, John N. Fobian, Yvette M. Benson, Timothy E. Moon, Joseph B. Bienkowski, Michael J. Brown, David L. Emmons, Thomas L. Heintz, Robert Laborde, Alice McDonald, Joseph J. Mischke, Brent V. Molyneaux, John M. Mullins, Patrick B. Bryan Prince, D. Paddock, Donna J. Tomasselli, Alfredo G. Winterrowd, Greg |
| description | We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of β-secretase that incorporate a variety of P
2 side chains that yield potent inhibitors with excellent cellular activity and good selectivity against Cathepsin-D.
We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of β-secretase that incorporates a variety of P
2 side chains that yield potent inhibitors with excellent cellular activity. A 2.2
Å crystal structure of compound
13 is shown. |
| doi_str_mv | 10.1016/j.bmcl.2006.09.091 |
| format | Article |
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2 side chains that yield potent inhibitors with excellent cellular activity and good selectivity against Cathepsin-D.
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2 side chains that yield potent inhibitors with excellent cellular activity. A 2.2
Å crystal structure of compound
13 is shown.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2006.09.091</identifier><identifier>PMID: 17049233</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Alzheimer Disease - drug therapy ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Amyloid Precursor Protein Secretases - chemistry ; Carbamates - chemical synthesis ; Carbamates - chemistry ; Carbamates - pharmacology ; Cells, Cultured ; Drug Design ; Humans ; Hydroxyethylamine (HEA) isostere ; Molecular Structure ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Structure-Activity Relationship ; Sulfonamides - chemical synthesis ; Sulfonamides - chemistry ; Sulfonamides - pharmacology ; β-Secretase</subject><ispartof>Bioorganic & medicinal chemistry letters, 2007, Vol.17 (1), p.78-81</ispartof><rights>2006 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-f2eb477a8c19f1bb24584d9ebce921b4f4afe8bad69217ce26387a0410e42b613</citedby><cites>FETCH-LOGICAL-c354t-f2eb477a8c19f1bb24584d9ebce921b4f4afe8bad69217ce26387a0410e42b613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X06011619$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,4010,27900,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17049233$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Freskos, John N.</creatorcontrib><creatorcontrib>Fobian, Yvette M.</creatorcontrib><creatorcontrib>Benson, Timothy E.</creatorcontrib><creatorcontrib>Moon, Joseph B.</creatorcontrib><creatorcontrib>Bienkowski, Michael J.</creatorcontrib><creatorcontrib>Brown, David L.</creatorcontrib><creatorcontrib>Emmons, Thomas L.</creatorcontrib><creatorcontrib>Heintz, Robert</creatorcontrib><creatorcontrib>Laborde, Alice</creatorcontrib><creatorcontrib>McDonald, Joseph J.</creatorcontrib><creatorcontrib>Mischke, Brent V.</creatorcontrib><creatorcontrib>Molyneaux, John M.</creatorcontrib><creatorcontrib>Mullins, Patrick B.</creatorcontrib><creatorcontrib>Bryan Prince, D.</creatorcontrib><creatorcontrib>Paddock, Donna J.</creatorcontrib><creatorcontrib>Tomasselli, Alfredo G.</creatorcontrib><creatorcontrib>Winterrowd, Greg</creatorcontrib><title>Design of potent inhibitors of human β-secretase. Part 2</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of β-secretase that incorporate a variety of P
2 side chains that yield potent inhibitors with excellent cellular activity and good selectivity against Cathepsin-D.
We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of β-secretase that incorporates a variety of P
2 side chains that yield potent inhibitors with excellent cellular activity. A 2.2
Å crystal structure of compound
13 is shown.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Amyloid Precursor Protein Secretases - chemistry</subject><subject>Carbamates - chemical synthesis</subject><subject>Carbamates - chemistry</subject><subject>Carbamates - pharmacology</subject><subject>Cells, Cultured</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Hydroxyethylamine (HEA) isostere</subject><subject>Molecular Structure</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><subject>β-Secretase</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1KxDAUhYMozjj6Ai6kK3etN2n6E3Aj_sOALhTchSS9dTL0Z0xSwdfyQXwmW2bAnXDgci_nHLgfIacUEgo0v1gnujVNwgDyBMQoukfmlOc8Tjlk-2QOIoe4FPxtRo68XwNQDpwfkhktgAuWpnMibtDb9y7q62jTB-xCZLuV1Tb0zk_H1dCqLvr5jj0ah0F5TKJn5ULEjslBrRqPJ7u5IK93ty_XD_Hy6f7x-moZmzTjIa4Zal4UqjRU1FRrxrOSVwK1QcGo5jVXNZZaVfm4FgZZnpaFAk4BOdM5TRfkfNu7cf3HgD7I1nqDTaM67Acv8zIVNGOTkW2NxvXeO6zlxtlWuS9JQU7A5FpOwOQETIIYNYXOdu2DbrH6i-wIjYbLrQHHHz8tOumNxc5gZR2aIKve_tf_C3Zce-8</recordid><startdate>2007</startdate><enddate>2007</enddate><creator>Freskos, John N.</creator><creator>Fobian, Yvette M.</creator><creator>Benson, Timothy E.</creator><creator>Moon, Joseph B.</creator><creator>Bienkowski, Michael J.</creator><creator>Brown, David L.</creator><creator>Emmons, Thomas L.</creator><creator>Heintz, Robert</creator><creator>Laborde, Alice</creator><creator>McDonald, Joseph J.</creator><creator>Mischke, Brent V.</creator><creator>Molyneaux, John M.</creator><creator>Mullins, Patrick B.</creator><creator>Bryan Prince, D.</creator><creator>Paddock, Donna J.</creator><creator>Tomasselli, Alfredo G.</creator><creator>Winterrowd, Greg</creator><general>Elsevier Ltd</general><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></search><sort><creationdate>2007</creationdate><title>Design of potent inhibitors of human β-secretase. Part 2</title><author>Freskos, John N. ; Fobian, Yvette M. ; Benson, Timothy E. ; Moon, Joseph B. ; Bienkowski, Michael J. ; Brown, David L. ; Emmons, Thomas L. ; Heintz, Robert ; Laborde, Alice ; McDonald, Joseph J. ; Mischke, Brent V. ; Molyneaux, John M. ; Mullins, Patrick B. ; Bryan Prince, D. ; Paddock, Donna J. ; Tomasselli, Alfredo G. ; Winterrowd, Greg</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-f2eb477a8c19f1bb24584d9ebce921b4f4afe8bad69217ce26387a0410e42b613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Amyloid Precursor Protein Secretases - chemistry</topic><topic>Carbamates - chemical synthesis</topic><topic>Carbamates - chemistry</topic><topic>Carbamates - pharmacology</topic><topic>Cells, Cultured</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Hydroxyethylamine (HEA) isostere</topic><topic>Molecular Structure</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><topic>β-Secretase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Freskos, John N.</creatorcontrib><creatorcontrib>Fobian, Yvette M.</creatorcontrib><creatorcontrib>Benson, Timothy E.</creatorcontrib><creatorcontrib>Moon, Joseph B.</creatorcontrib><creatorcontrib>Bienkowski, Michael J.</creatorcontrib><creatorcontrib>Brown, David L.</creatorcontrib><creatorcontrib>Emmons, Thomas L.</creatorcontrib><creatorcontrib>Heintz, Robert</creatorcontrib><creatorcontrib>Laborde, Alice</creatorcontrib><creatorcontrib>McDonald, Joseph J.</creatorcontrib><creatorcontrib>Mischke, Brent V.</creatorcontrib><creatorcontrib>Molyneaux, John M.</creatorcontrib><creatorcontrib>Mullins, Patrick B.</creatorcontrib><creatorcontrib>Bryan Prince, D.</creatorcontrib><creatorcontrib>Paddock, Donna J.</creatorcontrib><creatorcontrib>Tomasselli, Alfredo G.</creatorcontrib><creatorcontrib>Winterrowd, Greg</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Freskos, John N.</au><au>Fobian, Yvette M.</au><au>Benson, Timothy E.</au><au>Moon, Joseph B.</au><au>Bienkowski, Michael J.</au><au>Brown, David L.</au><au>Emmons, Thomas L.</au><au>Heintz, Robert</au><au>Laborde, Alice</au><au>McDonald, Joseph J.</au><au>Mischke, Brent V.</au><au>Molyneaux, John M.</au><au>Mullins, Patrick B.</au><au>Bryan Prince, D.</au><au>Paddock, Donna J.</au><au>Tomasselli, Alfredo G.</au><au>Winterrowd, Greg</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design of potent inhibitors of human β-secretase. Part 2</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2007</date><risdate>2007</risdate><volume>17</volume><issue>1</issue><spage>78</spage><epage>81</epage><pages>78-81</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of β-secretase that incorporate a variety of P
2 side chains that yield potent inhibitors with excellent cellular activity and good selectivity against Cathepsin-D.
We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of β-secretase that incorporates a variety of P
2 side chains that yield potent inhibitors with excellent cellular activity. A 2.2
Å crystal structure of compound
13 is shown.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>17049233</pmid><doi>10.1016/j.bmcl.2006.09.091</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2007, Vol.17 (1), p.78-81 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Alzheimer Disease - drug therapy Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - chemistry Carbamates - chemical synthesis Carbamates - chemistry Carbamates - pharmacology Cells, Cultured Drug Design Humans Hydroxyethylamine (HEA) isostere Molecular Structure Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology β-Secretase |
| title | Design of potent inhibitors of human β-secretase. Part 2 |
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