Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties
Molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype leading to MK-8133. [Display omitted] Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-06, Vol.25 (12), p.2488-2492 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Kuduk, Scott D. Skudlarek, Jason W. DiMarco, Christina N. Bruno, Joseph G. Pausch, Mark H. O’Brien, Julie A. Cabalu, Tamara D. Stevens, Joanne Brunner, Joseph Tannenbaum, Pamela L. Garson, Susan L. Savitz, Alan T. Harrell, Charles M. Gotter, Anthony L. Winrow, Christopher J. Renger, John J. Coleman, Paul J. |
| description | Molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype leading to MK-8133. [Display omitted]
Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties. |
| doi_str_mv | 10.1016/j.bmcl.2015.04.066 |
| format | Article |
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Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.04.066</identifier><identifier>PMID: 25981685</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antagonist ; Dogs ; GPCR ; Half-Life ; Insomnia ; Mice ; Orexin ; Orexin Receptor Antagonists - chemistry ; Orexin Receptor Antagonists - pharmacokinetics ; Orexin Receptor Antagonists - therapeutic use ; Orexin Receptors - chemistry ; Orexin Receptors - metabolism ; Piperidines - chemistry ; Piperidines - pharmacokinetics ; Piperidines - therapeutic use ; Protein Binding ; Pyrimidines - chemistry ; Rats ; Sleep ; Sleep Initiation and Maintenance Disorders - drug therapy ; Sleep Initiation and Maintenance Disorders - veterinary ; Structure-Activity Relationship ; Triazoles - chemistry ; Triazoles - pharmacokinetics ; Triazoles - therapeutic use</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-06, Vol.25 (12), p.2488-2492</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-757b1a9cb1aeca3ab07d9e01171d8cf9ec165ce51ab5bc5053df4290855576f33</citedby><cites>FETCH-LOGICAL-c426t-757b1a9cb1aeca3ab07d9e01171d8cf9ec165ce51ab5bc5053df4290855576f33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X15003984$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25981685$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kuduk, Scott D.</creatorcontrib><creatorcontrib>Skudlarek, Jason W.</creatorcontrib><creatorcontrib>DiMarco, Christina N.</creatorcontrib><creatorcontrib>Bruno, Joseph G.</creatorcontrib><creatorcontrib>Pausch, Mark H.</creatorcontrib><creatorcontrib>O’Brien, Julie A.</creatorcontrib><creatorcontrib>Cabalu, Tamara D.</creatorcontrib><creatorcontrib>Stevens, Joanne</creatorcontrib><creatorcontrib>Brunner, Joseph</creatorcontrib><creatorcontrib>Tannenbaum, Pamela L.</creatorcontrib><creatorcontrib>Garson, Susan L.</creatorcontrib><creatorcontrib>Savitz, Alan T.</creatorcontrib><creatorcontrib>Harrell, Charles M.</creatorcontrib><creatorcontrib>Gotter, Anthony L.</creatorcontrib><creatorcontrib>Winrow, Christopher J.</creatorcontrib><creatorcontrib>Renger, John J.</creatorcontrib><creatorcontrib>Coleman, Paul J.</creatorcontrib><title>Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype leading to MK-8133. [Display omitted]
Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.</description><subject>Animals</subject><subject>Antagonist</subject><subject>Dogs</subject><subject>GPCR</subject><subject>Half-Life</subject><subject>Insomnia</subject><subject>Mice</subject><subject>Orexin</subject><subject>Orexin Receptor Antagonists - chemistry</subject><subject>Orexin Receptor Antagonists - pharmacokinetics</subject><subject>Orexin Receptor Antagonists - therapeutic use</subject><subject>Orexin Receptors - chemistry</subject><subject>Orexin Receptors - metabolism</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - therapeutic use</subject><subject>Protein Binding</subject><subject>Pyrimidines - chemistry</subject><subject>Rats</subject><subject>Sleep</subject><subject>Sleep Initiation and Maintenance Disorders - drug therapy</subject><subject>Sleep Initiation and Maintenance Disorders - veterinary</subject><subject>Structure-Activity Relationship</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacokinetics</subject><subject>Triazoles - therapeutic use</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>eNp9kE9P3DAQxa2qCLbAF-ih8rGXhHH8J0nVC0LQIkBcWomb5TiT1qskTm3vAt--Xi1w5DKjkd57o_cj5DODkgFTZ-uym-xYVsBkCaIEpT6QFRNKFFyA_EhW0CoomlY8HJFPMa4BmAAhDslRJduGqUauyPq6xzm5wVmTnJ-pH-jdTdEwzr_R83wGfHJzUdGII9rktkgDWlySD9TMyfzxs4uJPrr0lw5m64PpRqQ9bnH0y5ST6RL8giE5jCfkYDBjxNOXfUx-X13-uvhZ3N7_uL44vy2sqFQqall3zLQ2D7SGmw7qvkVgrGZ9Y4cWLVPSomSmk52VIHk_iKqFRkpZq4HzY_J1n5tf_9tgTHpy0eI4mhn9JupcnHNZC1BZWu2lNvgYAw56CW4y4Vkz0DvGeq13jPWOsQahM-Ns-vKSv-km7N8sr1Cz4PtegLnl1mHQ0TqcLfYuw0u69-69_P9f5I5Q</recordid><startdate>20150615</startdate><enddate>20150615</enddate><creator>Kuduk, Scott D.</creator><creator>Skudlarek, Jason W.</creator><creator>DiMarco, Christina N.</creator><creator>Bruno, Joseph G.</creator><creator>Pausch, Mark H.</creator><creator>O’Brien, Julie A.</creator><creator>Cabalu, Tamara D.</creator><creator>Stevens, Joanne</creator><creator>Brunner, Joseph</creator><creator>Tannenbaum, Pamela L.</creator><creator>Garson, Susan L.</creator><creator>Savitz, Alan T.</creator><creator>Harrell, Charles M.</creator><creator>Gotter, Anthony L.</creator><creator>Winrow, Christopher J.</creator><creator>Renger, John J.</creator><creator>Coleman, Paul J.</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></search><sort><creationdate>20150615</creationdate><title>Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties</title><author>Kuduk, Scott D. ; Skudlarek, Jason W. ; DiMarco, Christina N. ; Bruno, Joseph G. ; Pausch, Mark H. ; O’Brien, Julie A. ; Cabalu, Tamara D. ; Stevens, Joanne ; Brunner, Joseph ; Tannenbaum, Pamela L. ; Garson, Susan L. ; Savitz, Alan T. ; Harrell, Charles M. ; Gotter, Anthony L. ; Winrow, Christopher J. ; Renger, John J. ; Coleman, Paul J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-757b1a9cb1aeca3ab07d9e01171d8cf9ec165ce51ab5bc5053df4290855576f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Antagonist</topic><topic>Dogs</topic><topic>GPCR</topic><topic>Half-Life</topic><topic>Insomnia</topic><topic>Mice</topic><topic>Orexin</topic><topic>Orexin Receptor Antagonists - chemistry</topic><topic>Orexin Receptor Antagonists - pharmacokinetics</topic><topic>Orexin Receptor Antagonists - therapeutic use</topic><topic>Orexin Receptors - chemistry</topic><topic>Orexin Receptors - metabolism</topic><topic>Piperidines - chemistry</topic><topic>Piperidines - pharmacokinetics</topic><topic>Piperidines - therapeutic use</topic><topic>Protein Binding</topic><topic>Pyrimidines - chemistry</topic><topic>Rats</topic><topic>Sleep</topic><topic>Sleep Initiation and Maintenance Disorders - drug therapy</topic><topic>Sleep Initiation and Maintenance Disorders - veterinary</topic><topic>Structure-Activity Relationship</topic><topic>Triazoles - chemistry</topic><topic>Triazoles - pharmacokinetics</topic><topic>Triazoles - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kuduk, Scott D.</creatorcontrib><creatorcontrib>Skudlarek, Jason W.</creatorcontrib><creatorcontrib>DiMarco, Christina N.</creatorcontrib><creatorcontrib>Bruno, Joseph G.</creatorcontrib><creatorcontrib>Pausch, Mark H.</creatorcontrib><creatorcontrib>O’Brien, Julie A.</creatorcontrib><creatorcontrib>Cabalu, Tamara D.</creatorcontrib><creatorcontrib>Stevens, Joanne</creatorcontrib><creatorcontrib>Brunner, Joseph</creatorcontrib><creatorcontrib>Tannenbaum, Pamela L.</creatorcontrib><creatorcontrib>Garson, Susan L.</creatorcontrib><creatorcontrib>Savitz, Alan T.</creatorcontrib><creatorcontrib>Harrell, Charles M.</creatorcontrib><creatorcontrib>Gotter, Anthony L.</creatorcontrib><creatorcontrib>Winrow, Christopher J.</creatorcontrib><creatorcontrib>Renger, John J.</creatorcontrib><creatorcontrib>Coleman, Paul J.</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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kuduk, Scott D.</au><au>Skudlarek, Jason W.</au><au>DiMarco, Christina N.</au><au>Bruno, Joseph G.</au><au>Pausch, Mark H.</au><au>O’Brien, Julie A.</au><au>Cabalu, Tamara D.</au><au>Stevens, Joanne</au><au>Brunner, Joseph</au><au>Tannenbaum, Pamela L.</au><au>Garson, Susan L.</au><au>Savitz, Alan T.</au><au>Harrell, Charles M.</au><au>Gotter, Anthony L.</au><au>Winrow, Christopher J.</au><au>Renger, John J.</au><au>Coleman, Paul J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-06-15</date><risdate>2015</risdate><volume>25</volume><issue>12</issue><spage>2488</spage><epage>2492</epage><pages>2488-2492</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype leading to MK-8133. [Display omitted]
Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25981685</pmid><doi>10.1016/j.bmcl.2015.04.066</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2015-06, Vol.25 (12), p.2488-2492 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Antagonist Dogs GPCR Half-Life Insomnia Mice Orexin Orexin Receptor Antagonists - chemistry Orexin Receptor Antagonists - pharmacokinetics Orexin Receptor Antagonists - therapeutic use Orexin Receptors - chemistry Orexin Receptors - metabolism Piperidines - chemistry Piperidines - pharmacokinetics Piperidines - therapeutic use Protein Binding Pyrimidines - chemistry Rats Sleep Sleep Initiation and Maintenance Disorders - drug therapy Sleep Initiation and Maintenance Disorders - veterinary Structure-Activity Relationship Triazoles - chemistry Triazoles - pharmacokinetics Triazoles - therapeutic use |
| title | Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties |
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