Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin
[Display omitted] Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medic...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (4), p.908-913 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 913 |
|---|---|
| container_issue | 4 |
| container_start_page | 908 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 25 |
| creator | Pettersson, Martin Johnson, Douglas S. Humphrey, John M. am Ende, Christopher W. Evrard, Edelweiss Efremov, Ivan Kauffman, Gregory W. Stepan, Antonia F. Stiff, Cory M. Xie, Longfei Bales, Kelly R. Hajos-Korcsok, Eva Murrey, Heather E. Pustilnik, Leslie R. Steyn, Stefanus J. Wood, Kathleen M. Verhoest, Patrick R. |
| description | [Display omitted]
Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex. |
| doi_str_mv | 10.1016/j.bmcl.2014.12.059 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1660404568</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X14013675</els_id><sourcerecordid>1660404568</sourcerecordid><originalsourceid>FETCH-LOGICAL-c459t-98b3afac62d423ec251f2a79660cd100932cdf12cda4f8893ad6730082cd03283</originalsourceid><addsrcrecordid>eNqNkcFKJDEQhoMo66zuC-xB-ujBtJV0OnbAi6i7Lgh72QVvIZNUuxm6O2OSGRhfy_fYZ9oMox5lL1VQfP8P9f-EfGVQM2DyfFHPRzvUHJioGa-hVXtkxoQUtBHQ7pMZKAm0U-LhkHxOaQEFBCE-kUPeth2XADNib3yyYY1xU4W-8pMLA1KH0a_RVctN9C6UaZ79hJSdSep8mLD6-0IT2ojZJKzG4FaDySGmKv8xucomPmKulhETTn7w0zE56M2Q8MvrPiK_v93-ur6j9z-__7i-uqdWtCpT1c0b0xsruRO8Qctb1nNzoaQE6xiAarh1PSvDiL7rVGOcvGgAunKBhnfNETnd-S5jeFphynosz-EwmAnDKmlWnEoArfwftOVCyE6xgvIdamNIKWKvl9GPJm40A73tQS_0tge97UEzrksPRXTy6r-aj-jeJW_BF-ByB2AJZO0x6mQ9Thadj2izdsF_5P8P_V-ajA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1652446891</pqid></control><display><type>article</type><title>Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin</title><source>MEDLINE</source><source>Access via ScienceDirect (Elsevier)</source><creator>Pettersson, Martin ; Johnson, Douglas S. ; Humphrey, John M. ; am Ende, Christopher W. ; Evrard, Edelweiss ; Efremov, Ivan ; Kauffman, Gregory W. ; Stepan, Antonia F. ; Stiff, Cory M. ; Xie, Longfei ; Bales, Kelly R. ; Hajos-Korcsok, Eva ; Murrey, Heather E. ; Pustilnik, Leslie R. ; Steyn, Stefanus J. ; Wood, Kathleen M. ; Verhoest, Patrick R.</creator><creatorcontrib>Pettersson, Martin ; Johnson, Douglas S. ; Humphrey, John M. ; am Ende, Christopher W. ; Evrard, Edelweiss ; Efremov, Ivan ; Kauffman, Gregory W. ; Stepan, Antonia F. ; Stiff, Cory M. ; Xie, Longfei ; Bales, Kelly R. ; Hajos-Korcsok, Eva ; Murrey, Heather E. ; Pustilnik, Leslie R. ; Steyn, Stefanus J. ; Wood, Kathleen M. ; Verhoest, Patrick R.</creatorcontrib><description>[Display omitted]
Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.12.059</identifier><identifier>PMID: 25582600</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Alzheimer’s disease ; Amyloid Precursor Protein Secretases - drug effects ; Animals ; Drug Discovery ; Indoles - chemistry ; Indoles - pharmacology ; Presenilins - drug effects ; Pyrazines - chemistry ; Rats ; γ-Secretase modulators</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (4), p.908-913</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-98b3afac62d423ec251f2a79660cd100932cdf12cda4f8893ad6730082cd03283</citedby><cites>FETCH-LOGICAL-c459t-98b3afac62d423ec251f2a79660cd100932cdf12cda4f8893ad6730082cd03283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2014.12.059$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25582600$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pettersson, Martin</creatorcontrib><creatorcontrib>Johnson, Douglas S.</creatorcontrib><creatorcontrib>Humphrey, John M.</creatorcontrib><creatorcontrib>am Ende, Christopher W.</creatorcontrib><creatorcontrib>Evrard, Edelweiss</creatorcontrib><creatorcontrib>Efremov, Ivan</creatorcontrib><creatorcontrib>Kauffman, Gregory W.</creatorcontrib><creatorcontrib>Stepan, Antonia F.</creatorcontrib><creatorcontrib>Stiff, Cory M.</creatorcontrib><creatorcontrib>Xie, Longfei</creatorcontrib><creatorcontrib>Bales, Kelly R.</creatorcontrib><creatorcontrib>Hajos-Korcsok, Eva</creatorcontrib><creatorcontrib>Murrey, Heather E.</creatorcontrib><creatorcontrib>Pustilnik, Leslie R.</creatorcontrib><creatorcontrib>Steyn, Stefanus J.</creatorcontrib><creatorcontrib>Wood, Kathleen M.</creatorcontrib><creatorcontrib>Verhoest, Patrick R.</creatorcontrib><title>Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.</description><subject>Alzheimer’s disease</subject><subject>Amyloid Precursor Protein Secretases - drug effects</subject><subject>Animals</subject><subject>Drug Discovery</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Presenilins - drug effects</subject><subject>Pyrazines - chemistry</subject><subject>Rats</subject><subject>γ-Secretase modulators</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFKJDEQhoMo66zuC-xB-ujBtJV0OnbAi6i7Lgh72QVvIZNUuxm6O2OSGRhfy_fYZ9oMox5lL1VQfP8P9f-EfGVQM2DyfFHPRzvUHJioGa-hVXtkxoQUtBHQ7pMZKAm0U-LhkHxOaQEFBCE-kUPeth2XADNib3yyYY1xU4W-8pMLA1KH0a_RVctN9C6UaZ79hJSdSep8mLD6-0IT2ojZJKzG4FaDySGmKv8xucomPmKulhETTn7w0zE56M2Q8MvrPiK_v93-ur6j9z-__7i-uqdWtCpT1c0b0xsruRO8Qctb1nNzoaQE6xiAarh1PSvDiL7rVGOcvGgAunKBhnfNETnd-S5jeFphynosz-EwmAnDKmlWnEoArfwftOVCyE6xgvIdamNIKWKvl9GPJm40A73tQS_0tge97UEzrksPRXTy6r-aj-jeJW_BF-ByB2AJZO0x6mQ9Thadj2izdsF_5P8P_V-ajA</recordid><startdate>20150215</startdate><enddate>20150215</enddate><creator>Pettersson, Martin</creator><creator>Johnson, Douglas S.</creator><creator>Humphrey, John M.</creator><creator>am Ende, Christopher W.</creator><creator>Evrard, Edelweiss</creator><creator>Efremov, Ivan</creator><creator>Kauffman, Gregory W.</creator><creator>Stepan, Antonia F.</creator><creator>Stiff, Cory M.</creator><creator>Xie, Longfei</creator><creator>Bales, Kelly R.</creator><creator>Hajos-Korcsok, Eva</creator><creator>Murrey, Heather E.</creator><creator>Pustilnik, Leslie R.</creator><creator>Steyn, Stefanus J.</creator><creator>Wood, Kathleen M.</creator><creator>Verhoest, Patrick R.</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20150215</creationdate><title>Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin</title><author>Pettersson, Martin ; Johnson, Douglas S. ; Humphrey, John M. ; am Ende, Christopher W. ; Evrard, Edelweiss ; Efremov, Ivan ; Kauffman, Gregory W. ; Stepan, Antonia F. ; Stiff, Cory M. ; Xie, Longfei ; Bales, Kelly R. ; Hajos-Korcsok, Eva ; Murrey, Heather E. ; Pustilnik, Leslie R. ; Steyn, Stefanus J. ; Wood, Kathleen M. ; Verhoest, Patrick R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-98b3afac62d423ec251f2a79660cd100932cdf12cda4f8893ad6730082cd03283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alzheimer’s disease</topic><topic>Amyloid Precursor Protein Secretases - drug effects</topic><topic>Animals</topic><topic>Drug Discovery</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Presenilins - drug effects</topic><topic>Pyrazines - chemistry</topic><topic>Rats</topic><topic>γ-Secretase modulators</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pettersson, Martin</creatorcontrib><creatorcontrib>Johnson, Douglas S.</creatorcontrib><creatorcontrib>Humphrey, John M.</creatorcontrib><creatorcontrib>am Ende, Christopher W.</creatorcontrib><creatorcontrib>Evrard, Edelweiss</creatorcontrib><creatorcontrib>Efremov, Ivan</creatorcontrib><creatorcontrib>Kauffman, Gregory W.</creatorcontrib><creatorcontrib>Stepan, Antonia F.</creatorcontrib><creatorcontrib>Stiff, Cory M.</creatorcontrib><creatorcontrib>Xie, Longfei</creatorcontrib><creatorcontrib>Bales, Kelly R.</creatorcontrib><creatorcontrib>Hajos-Korcsok, Eva</creatorcontrib><creatorcontrib>Murrey, Heather E.</creatorcontrib><creatorcontrib>Pustilnik, Leslie R.</creatorcontrib><creatorcontrib>Steyn, Stefanus J.</creatorcontrib><creatorcontrib>Wood, Kathleen M.</creatorcontrib><creatorcontrib>Verhoest, Patrick R.</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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pettersson, Martin</au><au>Johnson, Douglas S.</au><au>Humphrey, John M.</au><au>am Ende, Christopher W.</au><au>Evrard, Edelweiss</au><au>Efremov, Ivan</au><au>Kauffman, Gregory W.</au><au>Stepan, Antonia F.</au><au>Stiff, Cory M.</au><au>Xie, Longfei</au><au>Bales, Kelly R.</au><au>Hajos-Korcsok, Eva</au><au>Murrey, Heather E.</au><au>Pustilnik, Leslie R.</au><au>Steyn, Stefanus J.</au><au>Wood, Kathleen M.</au><au>Verhoest, Patrick R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-02-15</date><risdate>2015</risdate><volume>25</volume><issue>4</issue><spage>908</spage><epage>913</epage><pages>908-913</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25582600</pmid><doi>10.1016/j.bmcl.2014.12.059</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (4), p.908-913 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1660404568 |
| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Alzheimer’s disease Amyloid Precursor Protein Secretases - drug effects Animals Drug Discovery Indoles - chemistry Indoles - pharmacology Presenilins - drug effects Pyrazines - chemistry Rats γ-Secretase modulators |
| title | Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-21T12%3A35%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20indole-derived%20pyridopyrazine-1,6-dione%20%CE%B3-secretase%20modulators%20that%20target%20presenilin&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Pettersson,%20Martin&rft.date=2015-02-15&rft.volume=25&rft.issue=4&rft.spage=908&rft.epage=913&rft.pages=908-913&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2014.12.059&rft_dat=%3Cproquest_cross%3E1660404568%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1652446891&rft_id=info:pmid/25582600&rft_els_id=S0960894X14013675&rfr_iscdi=true |