Tricyclic imidazole antagonists of the Neuropeptide S Receptor
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. NPSR-PI1 demonstrates potent in vitro NPSR antagonism and central exposure in vivo. A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screenin...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (15), p.4704-4708 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Trotter, B. Wesley Nanda, Kausik K. Manley, Peter J. Uebele, Victor N. Condra, Cindra L. Gotter, Anthony L. Menzel, Karsten Henault, Martin Stocco, Rino Renger, John J. Hartman, George D. Bilodeau, Mark T. |
| description | A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. NPSR-PI1 demonstrates potent in vitro NPSR antagonism and central exposure in vivo.
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo. |
| doi_str_mv | 10.1016/j.bmcl.2010.04.016 |
| format | Article |
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A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.04.016</identifier><identifier>PMID: 20615693</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Biological and medical sciences ; Heterocyclic Compounds, 3-Ring - chemical synthesis ; Heterocyclic Compounds, 3-Ring - chemistry ; Heterocyclic Compounds, 3-Ring - pharmacology ; High-Throughput Screening Assays ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Medical sciences ; Neuropeptide S Receptor ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Rats ; Receptors, Neuropeptide - antagonists & inhibitors ; Receptors, Neuropeptide - metabolism ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-08, Vol.20 (15), p.4704-4708</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-22d8765665e49d7633a78a13952451c057e09b16f93796ba0d0827f4ff7337d63</citedby><cites>FETCH-LOGICAL-c417t-22d8765665e49d7633a78a13952451c057e09b16f93796ba0d0827f4ff7337d63</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.2010.04.016$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23066554$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20615693$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Trotter, B. Wesley</creatorcontrib><creatorcontrib>Nanda, Kausik K.</creatorcontrib><creatorcontrib>Manley, Peter J.</creatorcontrib><creatorcontrib>Uebele, Victor N.</creatorcontrib><creatorcontrib>Condra, Cindra L.</creatorcontrib><creatorcontrib>Gotter, Anthony L.</creatorcontrib><creatorcontrib>Menzel, Karsten</creatorcontrib><creatorcontrib>Henault, Martin</creatorcontrib><creatorcontrib>Stocco, Rino</creatorcontrib><creatorcontrib>Renger, John J.</creatorcontrib><creatorcontrib>Hartman, George D.</creatorcontrib><creatorcontrib>Bilodeau, Mark T.</creatorcontrib><title>Tricyclic imidazole antagonists of the Neuropeptide S Receptor</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. NPSR-PI1 demonstrates potent in vitro NPSR antagonism and central exposure in vivo.
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Heterocyclic Compounds, 3-Ring - chemical synthesis</subject><subject>Heterocyclic Compounds, 3-Ring - chemistry</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacology</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Neuropeptide S Receptor</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Receptors, Neuropeptide - antagonists & inhibitors</subject><subject>Receptors, Neuropeptide - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMtqHDEQRUVIiMePH8gi9MZ41ZNS69WCYDCDX2AS8AO8ExqpOtHQ3ZpIPQHn661hJskuWVVxOXUpDiEfKMwpUPlpNV8Orp83UALg8xK9ITPKJa8ZB_GWzEBLqFvNnw_IYc4rAMqB8_fkoAFJhdRsRs4fU3Avrg-uCkPw9lfssbLjZL_FMeQpV7Grpu9YfcFNimtcT8Fj9VDdoyt7TMfkXWf7jCf7eUSeri4fFzf13dfr28XFXe04VVPdNL5VUkgpkGuvJGNWtZYyLRouqAOhEPSSyk4zpeXSgoe2UR3vOsWY8pIdkbNd7zrFHxvMkxlCdtj3dsS4yUYJLkpbof9LMqZ1y1lTyGZHuhRzTtiZdQqDTS-GgtkKNiuzFWy2gg1wU6Jy9HFfv1kO6P-c_DZagNM9YLOzfZfs6EL-yzEoFgQv3Ocdh0Xbz4DJZBdwdOhDQjcZH8O__ngF88aW1g</recordid><startdate>20100801</startdate><enddate>20100801</enddate><creator>Trotter, B. 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Wesley ; Nanda, Kausik K. ; Manley, Peter J. ; Uebele, Victor N. ; Condra, Cindra L. ; Gotter, Anthony L. ; Menzel, Karsten ; Henault, Martin ; Stocco, Rino ; Renger, John J. ; Hartman, George D. ; Bilodeau, Mark T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-22d8765665e49d7633a78a13952451c057e09b16f93796ba0d0827f4ff7337d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Heterocyclic Compounds, 3-Ring - chemical synthesis</topic><topic>Heterocyclic Compounds, 3-Ring - chemistry</topic><topic>Heterocyclic Compounds, 3-Ring - pharmacology</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Neuropeptide S Receptor</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Receptors, Neuropeptide - antagonists & inhibitors</topic><topic>Receptors, Neuropeptide - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Trotter, B. 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Wesley</au><au>Nanda, Kausik K.</au><au>Manley, Peter J.</au><au>Uebele, Victor N.</au><au>Condra, Cindra L.</au><au>Gotter, Anthony L.</au><au>Menzel, Karsten</au><au>Henault, Martin</au><au>Stocco, Rino</au><au>Renger, John J.</au><au>Hartman, George D.</au><au>Bilodeau, Mark T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tricyclic imidazole antagonists of the Neuropeptide S Receptor</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-08-01</date><risdate>2010</risdate><volume>20</volume><issue>15</issue><spage>4704</spage><epage>4708</epage><pages>4704-4708</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. NPSR-PI1 demonstrates potent in vitro NPSR antagonism and central exposure in vivo.
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20615693</pmid><doi>10.1016/j.bmcl.2010.04.016</doi><tpages>5</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology High-Throughput Screening Assays Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Medical sciences Neuropeptide S Receptor Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Rats Receptors, Neuropeptide - antagonists & inhibitors Receptors, Neuropeptide - metabolism Structure-Activity Relationship |
| title | Tricyclic imidazole antagonists of the Neuropeptide S Receptor |
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