The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors
A novel series of GlyT-1 inhibitors is described. The most potent compound, 38, has a GlyT-1 b IC 50 = 59 nM. In vitro and in vivo assessment of CNS penetration showed that lead compounds had poor CNS exposure most likely due to active efflux by PgP transporters. Elevation of glycine levels by inhib...
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Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2006-08, Vol.16 (15), p.3981-3984 |
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container_issue | 15 |
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container_title | Bioorganic & medicinal chemistry letters |
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creator | Smith, Garrick Mikkelsen, Gitte Eskildsen, Jørgen Bundgaard, Christoffer |
description | A novel series of GlyT-1 inhibitors is described. The most potent compound,
38, has a GlyT-1
b IC
50
=
59
nM. In vitro and in vivo assessment of CNS penetration showed that lead compounds had poor CNS exposure most likely due to active efflux by PgP transporters.
Elevation of glycine levels by inhibition of the glycine transporter-1 (GlyT-1) and activation of the NMDA receptor is a potential strategy for the treatment of schizophrenia. A novel series of 2-arylsulfanylphenyl-1-oxyalkyl amino acids have been identified. The most prominent member of this series
S-1-{2-[3-(3-fluoro-phenylsulfanyl)biphenyl-4-yloxy]ethyl}pyrrolidine-2-carboxylic acid (
38) is a potent GlyT-1 inhibitor (IC
50
=
59
nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters. |
doi_str_mv | 10.1016/j.bmcl.2006.05.017 |
format | Article |
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38, has a GlyT-1
b IC
50
=
59
nM. In vitro and in vivo assessment of CNS penetration showed that lead compounds had poor CNS exposure most likely due to active efflux by PgP transporters.
Elevation of glycine levels by inhibition of the glycine transporter-1 (GlyT-1) and activation of the NMDA receptor is a potential strategy for the treatment of schizophrenia. A novel series of 2-arylsulfanylphenyl-1-oxyalkyl amino acids have been identified. The most prominent member of this series
S-1-{2-[3-(3-fluoro-phenylsulfanyl)biphenyl-4-yloxy]ethyl}pyrrolidine-2-carboxylic acid (
38) is a potent GlyT-1 inhibitor (IC
50
=
59
nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2006.05.017</identifier><identifier>PMID: 16725323</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Amino acids ; Amino Acids - chemical synthesis ; Amino Acids - chemistry ; Amino Acids - pharmacokinetics ; Amino Acids - pharmacology ; Biological and medical sciences ; Blood-Brain Barrier ; Caco-2 Cells ; Glutamatergic system (aspartate and other excitatory aminoacids) ; Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors ; Glycine transporter-1 ; GlyT-1 inhibitor ; Humans ; Medical sciences ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Psycholeptics: tranquillizer, neuroleptic ; Psychology. Psychoanalysis. Psychiatry ; Psychopharmacology ; Schizophrenia ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2006-08, Vol.16 (15), p.3981-3984</ispartof><rights>2006 Elsevier Ltd</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-57ae749bb12c30bdda1063d2afce10ffaf6fd30f12832a3dc6f038088c88edbb3</citedby><cites>FETCH-LOGICAL-c396t-57ae749bb12c30bdda1063d2afce10ffaf6fd30f12832a3dc6f038088c88edbb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X06005592$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17905257$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16725323$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smith, Garrick</creatorcontrib><creatorcontrib>Mikkelsen, Gitte</creatorcontrib><creatorcontrib>Eskildsen, Jørgen</creatorcontrib><creatorcontrib>Bundgaard, Christoffer</creatorcontrib><title>The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A novel series of GlyT-1 inhibitors is described. The most potent compound,
38, has a GlyT-1
b IC
50
=
59
nM. In vitro and in vivo assessment of CNS penetration showed that lead compounds had poor CNS exposure most likely due to active efflux by PgP transporters.
Elevation of glycine levels by inhibition of the glycine transporter-1 (GlyT-1) and activation of the NMDA receptor is a potential strategy for the treatment of schizophrenia. A novel series of 2-arylsulfanylphenyl-1-oxyalkyl amino acids have been identified. The most prominent member of this series
S-1-{2-[3-(3-fluoro-phenylsulfanyl)biphenyl-4-yloxy]ethyl}pyrrolidine-2-carboxylic acid (
38) is a potent GlyT-1 inhibitor (IC
50
=
59
nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters.</description><subject>Amino acids</subject><subject>Amino Acids - chemical synthesis</subject><subject>Amino Acids - chemistry</subject><subject>Amino Acids - pharmacokinetics</subject><subject>Amino Acids - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Blood-Brain Barrier</subject><subject>Caco-2 Cells</subject><subject>Glutamatergic system (aspartate and other excitatory aminoacids)</subject><subject>Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors</subject><subject>Glycine transporter-1</subject><subject>GlyT-1 inhibitor</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Psycholeptics: tranquillizer, neuroleptic</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Schizophrenia</subject><subject>Structure-Activity Relationship</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>eNqFkE2LFDEURYMoTjv6B1xIbXSX8uWzqsDNMOgoDAjawuxCKnmh06aq2qRarH9vNd0wO928uzn38jiEvGZQM2D6_b7uB5dqDqBrUDWw5gnZMKklFRLUU7KBTgNtO_lwRV6UsgdgEqR8Tq6YbrgSXGzIw3aHVVnGeYcllsqOvvp-862aQsWpzUsqxxTsuKTDDtdLGZ3-LDb9XJId4jhV1kW_tkp1l5YtZVUcd7GP85TLS_Is2FTw1SWvyY9PH7e3n-n917svtzf31IlOz1Q1FhvZ9T3jTkDvvWWghec2OGQQgg06eAGB8VZwK7zTAUQLbevaFn3fi2vy7rx7yNOvI5bZDLE4TMmOOB2L0S10qhHwX5A1nHGl5AryM-jyVErGYA45DqsMw8CcxJu9OYk3J_EGlFnFr6U3l_VjP6B_rFxMr8DbC2CLsylkO7pYHrmmA8XVaejDmcNV2u-I2RQXcXToY0Y3Gz_Ff_3xF-HsoZs</recordid><startdate>20060801</startdate><enddate>20060801</enddate><creator>Smith, Garrick</creator><creator>Mikkelsen, Gitte</creator><creator>Eskildsen, Jørgen</creator><creator>Bundgaard, Christoffer</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>20060801</creationdate><title>The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors</title><author>Smith, Garrick ; Mikkelsen, Gitte ; Eskildsen, Jørgen ; Bundgaard, Christoffer</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-57ae749bb12c30bdda1063d2afce10ffaf6fd30f12832a3dc6f038088c88edbb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Amino acids</topic><topic>Amino Acids - chemical synthesis</topic><topic>Amino Acids - chemistry</topic><topic>Amino Acids - pharmacokinetics</topic><topic>Amino Acids - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Blood-Brain Barrier</topic><topic>Caco-2 Cells</topic><topic>Glutamatergic system (aspartate and other excitatory aminoacids)</topic><topic>Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors</topic><topic>Glycine transporter-1</topic><topic>GlyT-1 inhibitor</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Psycholeptics: tranquillizer, neuroleptic</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Schizophrenia</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smith, Garrick</creatorcontrib><creatorcontrib>Mikkelsen, Gitte</creatorcontrib><creatorcontrib>Eskildsen, Jørgen</creatorcontrib><creatorcontrib>Bundgaard, Christoffer</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>Smith, Garrick</au><au>Mikkelsen, Gitte</au><au>Eskildsen, Jørgen</au><au>Bundgaard, Christoffer</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2006-08-01</date><risdate>2006</risdate><volume>16</volume><issue>15</issue><spage>3981</spage><epage>3984</epage><pages>3981-3984</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A novel series of GlyT-1 inhibitors is described. The most potent compound,
38, has a GlyT-1
b IC
50
=
59
nM. In vitro and in vivo assessment of CNS penetration showed that lead compounds had poor CNS exposure most likely due to active efflux by PgP transporters.
Elevation of glycine levels by inhibition of the glycine transporter-1 (GlyT-1) and activation of the NMDA receptor is a potential strategy for the treatment of schizophrenia. A novel series of 2-arylsulfanylphenyl-1-oxyalkyl amino acids have been identified. The most prominent member of this series
S-1-{2-[3-(3-fluoro-phenylsulfanyl)biphenyl-4-yloxy]ethyl}pyrrolidine-2-carboxylic acid (
38) is a potent GlyT-1 inhibitor (IC
50
=
59
nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>16725323</pmid><doi>10.1016/j.bmcl.2006.05.017</doi><tpages>4</tpages></addata></record> |
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source | MEDLINE; Elsevier ScienceDirect Journals |
subjects | Amino acids Amino Acids - chemical synthesis Amino Acids - chemistry Amino Acids - pharmacokinetics Amino Acids - pharmacology Biological and medical sciences Blood-Brain Barrier Caco-2 Cells Glutamatergic system (aspartate and other excitatory aminoacids) Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors Glycine transporter-1 GlyT-1 inhibitor Humans Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Psycholeptics: tranquillizer, neuroleptic Psychology. Psychoanalysis. Psychiatry Psychopharmacology Schizophrenia Structure-Activity Relationship |
title | The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors |
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