Synthesis and evaluation of succinoyl-caprolactam γ-secretase inhibitors
The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described. The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-sec...
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Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2006-05, Vol.16 (9), p.2357-2363 |
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creator | Thompson, Lorin A. Liauw, Ann Y. Ramanjulu, Mercy M. Kasireddy-Polam, Padmaja Mercer, Stephen E. Maduskuie, Thomas P. Glicksman, Marcie Roach, Arthur H. Meredith, Jere E. Liu, Rui-Qin Combs, Andrew P. Higaki, Jeffrey N. Cordell, Barbara Seiffert, Dietmar Zaczek, Robert C. Robertson, David W. Olson, Richard E. |
description | The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described.
The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of γ-secretase and high potency in cellular assays of Aβ reduction. The SAR and early in vivo properties of this series of inhibitors will be presented. |
doi_str_mv | 10.1016/j.bmcl.2006.01.055 |
format | Article |
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The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of γ-secretase and high potency in cellular assays of Aβ reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2006.01.055</identifier><identifier>PMID: 16473009</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Alzheimer Disease - drug therapy ; Alzheimer Disease - enzymology ; Alzheimer’s disease ; Amyloid Precursor Protein Secretases ; Animals ; Aspartic Acid Endopeptidases ; Biological and medical sciences ; Caprolactam - analogs & derivatives ; Caprolactam - chemistry ; Cell Line ; Dogs ; Drug Design ; Drug Evaluation, Preclinical ; Endopeptidases - chemistry ; Endopeptidases - drug effects ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; Medical sciences ; Molecular Conformation ; Neuropharmacology ; Pharmacology. Drug treatments ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Stereoisomerism ; Structure-Activity Relationship ; Succinates - chemistry ; β-Amyloid production inhibitors ; γ-Secretase inhibitors</subject><ispartof>Bioorganic & medicinal chemistry letters, 2006-05, Vol.16 (9), p.2357-2363</ispartof><rights>2006 Elsevier Ltd</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-cdc42fe8928fa6974a400a774639b137f88608efd182e11048fa1f38f438ee953</citedby><cites>FETCH-LOGICAL-c415t-cdc42fe8928fa6974a400a774639b137f88608efd182e11048fa1f38f438ee953</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X06000977$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17619126$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16473009$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thompson, Lorin A.</creatorcontrib><creatorcontrib>Liauw, Ann Y.</creatorcontrib><creatorcontrib>Ramanjulu, Mercy M.</creatorcontrib><creatorcontrib>Kasireddy-Polam, Padmaja</creatorcontrib><creatorcontrib>Mercer, Stephen E.</creatorcontrib><creatorcontrib>Maduskuie, Thomas P.</creatorcontrib><creatorcontrib>Glicksman, Marcie</creatorcontrib><creatorcontrib>Roach, Arthur H.</creatorcontrib><creatorcontrib>Meredith, Jere E.</creatorcontrib><creatorcontrib>Liu, Rui-Qin</creatorcontrib><creatorcontrib>Combs, Andrew P.</creatorcontrib><creatorcontrib>Higaki, Jeffrey N.</creatorcontrib><creatorcontrib>Cordell, Barbara</creatorcontrib><creatorcontrib>Seiffert, Dietmar</creatorcontrib><creatorcontrib>Zaczek, Robert C.</creatorcontrib><creatorcontrib>Robertson, David W.</creatorcontrib><creatorcontrib>Olson, Richard E.</creatorcontrib><title>Synthesis and evaluation of succinoyl-caprolactam γ-secretase inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described.
The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of γ-secretase and high potency in cellular assays of Aβ reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.</description><subject>Alzheimer Disease - drug therapy</subject><subject>Alzheimer Disease - enzymology</subject><subject>Alzheimer’s disease</subject><subject>Amyloid Precursor Protein Secretases</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases</subject><subject>Biological and medical sciences</subject><subject>Caprolactam - analogs & derivatives</subject><subject>Caprolactam - chemistry</subject><subject>Cell Line</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Drug Evaluation, Preclinical</subject><subject>Endopeptidases - chemistry</subject><subject>Endopeptidases - drug effects</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Molecular Conformation</subject><subject>Neuropharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Succinates - chemistry</subject><subject>β-Amyloid production inhibitors</subject><subject>γ-Secretase inhibitors</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>eNqF0M1KHEEQwPEmROKqeYEcwlyS24xVMz39AV5EjBGEHEzAW9PbU429zIfpnhH2uXwPn8ledsFbcqrLr4riz9gXhAoBxfmmWg-ur2oAUQFW0LYf2Aq54GXDof3IVqAFlErzh2N2ktIGADlw_okdo-CyAdArdnu_HedHSiEVduwKerb9YucwjcXki7Q4F8Zp25fOPsWpt262Q_H6UiZykWabqAjjY1iHeYrpjB152yf6fJin7M-P699XP8u7Xze3V5d3pePYzqXrHK89KV0rb4WW3HIAKyUXjV5jI71SAhT5DlVNiMAzQ98ozxtFpNvmlH3f380f_V0ozWYIyVHf25GmJRkhpUDV4n8hSlCy1TzDeg9dnFKK5M1TDIONW4NgdqXNxuxKm11pA2hy6bz09XB9WQ_Uva8c0mbw7QBscrb30Y4upHeXv9RYi-wu9o5ytOdA0SQXaHTUhUhuNt0U_vXHGwPznNs</recordid><startdate>20060501</startdate><enddate>20060501</enddate><creator>Thompson, Lorin A.</creator><creator>Liauw, Ann Y.</creator><creator>Ramanjulu, Mercy M.</creator><creator>Kasireddy-Polam, Padmaja</creator><creator>Mercer, Stephen E.</creator><creator>Maduskuie, Thomas P.</creator><creator>Glicksman, Marcie</creator><creator>Roach, Arthur H.</creator><creator>Meredith, Jere E.</creator><creator>Liu, Rui-Qin</creator><creator>Combs, Andrew P.</creator><creator>Higaki, Jeffrey N.</creator><creator>Cordell, Barbara</creator><creator>Seiffert, Dietmar</creator><creator>Zaczek, Robert C.</creator><creator>Robertson, David W.</creator><creator>Olson, Richard E.</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060501</creationdate><title>Synthesis and evaluation of succinoyl-caprolactam γ-secretase inhibitors</title><author>Thompson, Lorin A. ; Liauw, Ann Y. ; Ramanjulu, Mercy M. ; Kasireddy-Polam, Padmaja ; Mercer, Stephen E. ; Maduskuie, Thomas P. ; Glicksman, Marcie ; Roach, Arthur H. ; Meredith, Jere E. ; Liu, Rui-Qin ; Combs, Andrew P. ; Higaki, Jeffrey N. ; Cordell, Barbara ; Seiffert, Dietmar ; Zaczek, Robert C. ; Robertson, David W. ; Olson, Richard E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-cdc42fe8928fa6974a400a774639b137f88608efd182e11048fa1f38f438ee953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Alzheimer Disease - drug therapy</topic><topic>Alzheimer Disease - enzymology</topic><topic>Alzheimer’s disease</topic><topic>Amyloid Precursor Protein Secretases</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases</topic><topic>Biological and medical sciences</topic><topic>Caprolactam - analogs & derivatives</topic><topic>Caprolactam - chemistry</topic><topic>Cell Line</topic><topic>Dogs</topic><topic>Drug Design</topic><topic>Drug Evaluation, Preclinical</topic><topic>Endopeptidases - chemistry</topic><topic>Endopeptidases - drug effects</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Molecular Conformation</topic><topic>Neuropharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Succinates - chemistry</topic><topic>β-Amyloid production inhibitors</topic><topic>γ-Secretase inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Thompson, Lorin A.</creatorcontrib><creatorcontrib>Liauw, Ann Y.</creatorcontrib><creatorcontrib>Ramanjulu, Mercy M.</creatorcontrib><creatorcontrib>Kasireddy-Polam, Padmaja</creatorcontrib><creatorcontrib>Mercer, Stephen E.</creatorcontrib><creatorcontrib>Maduskuie, Thomas P.</creatorcontrib><creatorcontrib>Glicksman, Marcie</creatorcontrib><creatorcontrib>Roach, Arthur H.</creatorcontrib><creatorcontrib>Meredith, Jere E.</creatorcontrib><creatorcontrib>Liu, Rui-Qin</creatorcontrib><creatorcontrib>Combs, Andrew P.</creatorcontrib><creatorcontrib>Higaki, Jeffrey N.</creatorcontrib><creatorcontrib>Cordell, Barbara</creatorcontrib><creatorcontrib>Seiffert, Dietmar</creatorcontrib><creatorcontrib>Zaczek, Robert C.</creatorcontrib><creatorcontrib>Robertson, David W.</creatorcontrib><creatorcontrib>Olson, Richard E.</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thompson, Lorin A.</au><au>Liauw, Ann Y.</au><au>Ramanjulu, Mercy M.</au><au>Kasireddy-Polam, Padmaja</au><au>Mercer, Stephen E.</au><au>Maduskuie, Thomas P.</au><au>Glicksman, Marcie</au><au>Roach, Arthur H.</au><au>Meredith, Jere E.</au><au>Liu, Rui-Qin</au><au>Combs, Andrew P.</au><au>Higaki, Jeffrey N.</au><au>Cordell, Barbara</au><au>Seiffert, Dietmar</au><au>Zaczek, Robert C.</au><au>Robertson, David W.</au><au>Olson, Richard E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of succinoyl-caprolactam γ-secretase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2006-05-01</date><risdate>2006</risdate><volume>16</volume><issue>9</issue><spage>2357</spage><epage>2363</epage><pages>2357-2363</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described.
The synthesis, evaluation, and structure–activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer’s disease γ-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of γ-secretase and high potency in cellular assays of Aβ reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>16473009</pmid><doi>10.1016/j.bmcl.2006.01.055</doi><tpages>7</tpages></addata></record> |
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subjects | Alzheimer Disease - drug therapy Alzheimer Disease - enzymology Alzheimer’s disease Amyloid Precursor Protein Secretases Animals Aspartic Acid Endopeptidases Biological and medical sciences Caprolactam - analogs & derivatives Caprolactam - chemistry Cell Line Dogs Drug Design Drug Evaluation, Preclinical Endopeptidases - chemistry Endopeptidases - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Medical sciences Molecular Conformation Neuropharmacology Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Stereoisomerism Structure-Activity Relationship Succinates - chemistry β-Amyloid production inhibitors γ-Secretase inhibitors |
title | Synthesis and evaluation of succinoyl-caprolactam γ-secretase inhibitors |
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