BACE-1 inhibition by a series of ψ[CH 2NH] reduced amide isosteres
A new class of β-secretase inhibitors that incorporate a reduced amide transition state isostere as the key binding element is described. The incorporation of a 5-substituted isophthalamide scaffold at the N-terminal site of this isostere resulted in potent compounds that display impressive cellular...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2006-07, Vol.16 (14), p.3635-3638 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Coburn, Craig A. Stachel, Shawn J. Jones, Kristen G. Steele, Thomas G. Rush, Diane M. DiMuzio, Jillian Pietrak, Beth L. Lai, Ming-Tain Huang, Qian Lineberger, Janet Jin, Lixia Munshi, Sanjeev Katharine Holloway, M. Espeseth, Amy Simon, Adam Hazuda, Daria Graham, Samuel L. Vacca, Joseph P. |
| description | A new class of β-secretase inhibitors that incorporate a reduced amide transition state isostere as the key binding element is described. The incorporation of a 5-substituted isophthalamide scaffold at the N-terminal site of this isostere resulted in potent compounds that display impressive cellular IC
50 values. The syntheses and BACE-1 activities of these inhibitors are reported.
A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH
2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay. |
| doi_str_mv | 10.1016/j.bmcl.2006.04.076 |
| format | Article |
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A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH
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50 values. The syntheses and BACE-1 activities of these inhibitors are reported.
A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH
2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.</description><subject>Amides - chemistry</subject><subject>Amyloid Precursor Protein Secretases</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Endopeptidases - metabolism</subject><subject>Immunoassay</subject><subject>Isostere</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Peptides - chemistry</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Reduced amide</subject><subject>Structure-Activity Relationship</subject><subject>β-Secretase</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM9q3DAQh0VJaDZJX6CHokt6szNajWUbeklM0g0sySWFQAhClsZUi_-kkreQN-jb9ZWqZRdy62kY-H6_GT7GPgvIBQh1ucnbwfb5EkDlgDmU6gNbCFSYSYTiiC2gVpBVNT6dsNMYNwACAfEjOxFK1SAFLlhzfdXcZIL78adv_eynkbdv3PBIwVPkU8f__nluVnx5v3rhgdzWkuNm8I64j1OcKVA8Z8ed6SN9Oswz9uP25rFZZeuH73fN1TqzssI5E4UrBbZ1Ol2hAnLklGk7W0lZt7VBLFVtVVehQ-nQKmxRKihsWkqjyMgz9nXf-xqmX1uKsx58tNT3ZqRpG7WqAEEqTOByD9owxRio06_BDya8aQF6p05v9E6d3qnTgDqpS6Evh_ZtO5B7jxxcJeDiAJhoTd8FM1of37myKqAUReK-7TlKLn57CjpaT2MS5wPZWbvJ_--Pf0wrim8</recordid><startdate>20060715</startdate><enddate>20060715</enddate><creator>Coburn, Craig A.</creator><creator>Stachel, Shawn J.</creator><creator>Jones, Kristen G.</creator><creator>Steele, Thomas G.</creator><creator>Rush, Diane M.</creator><creator>DiMuzio, Jillian</creator><creator>Pietrak, Beth L.</creator><creator>Lai, Ming-Tain</creator><creator>Huang, Qian</creator><creator>Lineberger, Janet</creator><creator>Jin, Lixia</creator><creator>Munshi, Sanjeev</creator><creator>Katharine Holloway, M.</creator><creator>Espeseth, Amy</creator><creator>Simon, Adam</creator><creator>Hazuda, Daria</creator><creator>Graham, Samuel L.</creator><creator>Vacca, Joseph P.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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></search><sort><creationdate>20060715</creationdate><title>BACE-1 inhibition by a series of ψ[CH 2NH] reduced amide isosteres</title><author>Coburn, Craig A. ; Stachel, Shawn J. ; Jones, Kristen G. ; Steele, Thomas G. ; Rush, Diane M. ; DiMuzio, Jillian ; Pietrak, Beth L. ; Lai, Ming-Tain ; Huang, Qian ; Lineberger, Janet ; Jin, Lixia ; Munshi, Sanjeev ; Katharine Holloway, M. ; Espeseth, Amy ; Simon, Adam ; Hazuda, Daria ; Graham, Samuel L. ; Vacca, Joseph P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-15d714b96908460eded6abfc8339b9a44769c6f84d43d4c64b43605c3d47a6ea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Amides - chemistry</topic><topic>Amyloid Precursor Protein Secretases</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Endopeptidases - metabolism</topic><topic>Immunoassay</topic><topic>Isostere</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Peptides - chemistry</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Reduced amide</topic><topic>Structure-Activity Relationship</topic><topic>β-Secretase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Coburn, Craig A.</creatorcontrib><creatorcontrib>Stachel, Shawn J.</creatorcontrib><creatorcontrib>Jones, Kristen G.</creatorcontrib><creatorcontrib>Steele, Thomas G.</creatorcontrib><creatorcontrib>Rush, Diane M.</creatorcontrib><creatorcontrib>DiMuzio, Jillian</creatorcontrib><creatorcontrib>Pietrak, Beth L.</creatorcontrib><creatorcontrib>Lai, Ming-Tain</creatorcontrib><creatorcontrib>Huang, Qian</creatorcontrib><creatorcontrib>Lineberger, Janet</creatorcontrib><creatorcontrib>Jin, Lixia</creatorcontrib><creatorcontrib>Munshi, Sanjeev</creatorcontrib><creatorcontrib>Katharine Holloway, M.</creatorcontrib><creatorcontrib>Espeseth, Amy</creatorcontrib><creatorcontrib>Simon, Adam</creatorcontrib><creatorcontrib>Hazuda, Daria</creatorcontrib><creatorcontrib>Graham, Samuel L.</creatorcontrib><creatorcontrib>Vacca, Joseph P.</creatorcontrib><collection>Pascal-Francis</collection><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>Coburn, Craig A.</au><au>Stachel, Shawn J.</au><au>Jones, Kristen G.</au><au>Steele, Thomas G.</au><au>Rush, Diane M.</au><au>DiMuzio, Jillian</au><au>Pietrak, Beth L.</au><au>Lai, Ming-Tain</au><au>Huang, Qian</au><au>Lineberger, Janet</au><au>Jin, Lixia</au><au>Munshi, Sanjeev</au><au>Katharine Holloway, M.</au><au>Espeseth, Amy</au><au>Simon, Adam</au><au>Hazuda, Daria</au><au>Graham, Samuel L.</au><au>Vacca, Joseph P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BACE-1 inhibition by a series of ψ[CH 2NH] reduced amide isosteres</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2006-07-15</date><risdate>2006</risdate><volume>16</volume><issue>14</issue><spage>3635</spage><epage>3638</epage><pages>3635-3638</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A new class of β-secretase inhibitors that incorporate a reduced amide transition state isostere as the key binding element is described. The incorporation of a 5-substituted isophthalamide scaffold at the N-terminal site of this isostere resulted in potent compounds that display impressive cellular IC
50 values. The syntheses and BACE-1 activities of these inhibitors are reported.
A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH
2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>16690314</pmid><doi>10.1016/j.bmcl.2006.04.076</doi><tpages>4</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2006-07, Vol.16 (14), p.3635-3638 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_68040364 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Amides - chemistry Amyloid Precursor Protein Secretases Binding Sites Biological and medical sciences Endopeptidases - metabolism Immunoassay Isostere Medical sciences Neuropharmacology Peptides - chemistry Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - pharmacology Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Reduced amide Structure-Activity Relationship β-Secretase |
| title | BACE-1 inhibition by a series of ψ[CH 2NH] reduced amide isosteres |
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