Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease
Structure–activity relationships within the indole‐3‐glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC50
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| Veröffentlicht in: | ChemMedChem 2011-01, Vol.6 (1), p.115-130 |
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| creator | Thompson, Mark J. Louth, Jennifer C. Ferrara, Steven Sorrell, Fiona J. Irving, Benjamin J. Cochrane, Edward J. Meijer, Anthony J. H. M. Chen, Beining |
| description | Structure–activity relationships within the indole‐3‐glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC50 |
| doi_str_mv | 10.1002/cmdc.201000383 |
| format | Article |
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Making mad cows a myth! The indole‐3‐glyoxylamide series of antiprion agents has been further optimised, and characteristics contributing to their activity have been identified by computational studies. Varying the glyoxylamide motif or introducing substitution at N‐1 gave analogues with lower efficacy.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201000383</identifier><identifier>PMID: 21154498</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>Animals ; Cell Line ; drug discovery ; High-Throughput Screening Assays ; indoles ; Indoles - chemistry ; Kinetics ; Ligands ; medicinal chemistry ; Mice ; Models, Molecular ; prion disease ; Prion Diseases - drug therapy ; Prions - antagonists & inhibitors ; Prions - metabolism ; Protein Conformation ; Quantitative Structure-Activity Relationship ; Small Molecule Libraries - metabolism ; Small Molecule Libraries - pharmacology ; structure-activity relationships ; Sulfonylurea Compounds - chemistry</subject><ispartof>ChemMedChem, 2011-01, Vol.6 (1), p.115-130</ispartof><rights>Copyright © 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3823-eb0dec8238e773be6dd568766d2b801b0a3a87baea465453cb010e3408f74aae3</citedby><cites>FETCH-LOGICAL-c3823-eb0dec8238e773be6dd568766d2b801b0a3a87baea465453cb010e3408f74aae3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201000383$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201000383$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1416,27922,27923,45572,45573</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21154498$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thompson, Mark J.</creatorcontrib><creatorcontrib>Louth, Jennifer C.</creatorcontrib><creatorcontrib>Ferrara, Steven</creatorcontrib><creatorcontrib>Sorrell, Fiona J.</creatorcontrib><creatorcontrib>Irving, Benjamin J.</creatorcontrib><creatorcontrib>Cochrane, Edward J.</creatorcontrib><creatorcontrib>Meijer, Anthony J. H. M.</creatorcontrib><creatorcontrib>Chen, Beining</creatorcontrib><title>Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>Structure–activity relationships within the indole‐3‐glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC50 <10 nM). After examining a range of substituents at the para‐position of the N‐phenylglyoxylamide moiety, five‐membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie‐infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole‐3‐glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.
Making mad cows a myth! The indole‐3‐glyoxylamide series of antiprion agents has been further optimised, and characteristics contributing to their activity have been identified by computational studies. Varying the glyoxylamide motif or introducing substitution at N‐1 gave analogues with lower efficacy.</description><subject>Animals</subject><subject>Cell Line</subject><subject>drug discovery</subject><subject>High-Throughput Screening Assays</subject><subject>indoles</subject><subject>Indoles - chemistry</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>medicinal chemistry</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>prion disease</subject><subject>Prion Diseases - drug therapy</subject><subject>Prions - antagonists & inhibitors</subject><subject>Prions - metabolism</subject><subject>Protein Conformation</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Small Molecule Libraries - metabolism</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>structure-activity relationships</subject><subject>Sulfonylurea Compounds - chemistry</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM1v1DAQxS0EoqVw5Yh845StHSex97hN6Ye0fBbUo-XYk9aQj63HgebavxwvW1bckEaaN6P33uFHyGvOFpyx_Nj2zi5yljQTSjwhh1xVLJNcyad7LZcH5AXid8aKQnH1nBzknJdFsVSH5OEqhsnGKUC2stH_9HGmX6Az0Y8D3vpNOlo_QA9DpGZw9GwK8RYCXSEC4p_32NLLwY0dZCK76ebxfu5M7x0gNWnoGoyjVxD89nFj_ICRfgqpnp56BIPwkjxrTYfw6nEfkW9n777WF9n64_llvVpnVqhcZNAwBzYpBVKKBirnykrJqnJ5oxhvmBFGycaAKaqyKIVtEhUQBVOtLIwBcUTe7no3YbybAKPuPVroOjPAOKFWOS-XVa54ci52ThtGxACt3gTfmzBrzvQWu95i13vsKfDmsXpqenB7-1_OybDcGX75Dub_1On6_Wn9b3m2y3qMcL_PmvBDV1LIUl9_ONcXrOb85POJvha_AXBan80</recordid><startdate>20110103</startdate><enddate>20110103</enddate><creator>Thompson, Mark J.</creator><creator>Louth, Jennifer C.</creator><creator>Ferrara, Steven</creator><creator>Sorrell, Fiona J.</creator><creator>Irving, Benjamin J.</creator><creator>Cochrane, Edward J.</creator><creator>Meijer, Anthony J. H. M.</creator><creator>Chen, Beining</creator><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><scope>BSCLL</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>20110103</creationdate><title>Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease</title><author>Thompson, Mark J. ; Louth, Jennifer C. ; Ferrara, Steven ; Sorrell, Fiona J. ; Irving, Benjamin J. ; Cochrane, Edward J. ; Meijer, Anthony J. H. 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M.</au><au>Chen, Beining</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2011-01-03</date><risdate>2011</risdate><volume>6</volume><issue>1</issue><spage>115</spage><epage>130</epage><pages>115-130</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>Structure–activity relationships within the indole‐3‐glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC50 <10 nM). After examining a range of substituents at the para‐position of the N‐phenylglyoxylamide moiety, five‐membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie‐infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole‐3‐glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.
Making mad cows a myth! The indole‐3‐glyoxylamide series of antiprion agents has been further optimised, and characteristics contributing to their activity have been identified by computational studies. Varying the glyoxylamide motif or introducing substitution at N‐1 gave analogues with lower efficacy.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>21154498</pmid><doi>10.1002/cmdc.201000383</doi><tpages>16</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library All Journals |
| subjects | Animals Cell Line drug discovery High-Throughput Screening Assays indoles Indoles - chemistry Kinetics Ligands medicinal chemistry Mice Models, Molecular prion disease Prion Diseases - drug therapy Prions - antagonists & inhibitors Prions - metabolism Protein Conformation Quantitative Structure-Activity Relationship Small Molecule Libraries - metabolism Small Molecule Libraries - pharmacology structure-activity relationships Sulfonylurea Compounds - chemistry |
| title | Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease |
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