Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists
[Display omitted] The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properti...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (16), p.3157-3163 |
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| creator | Rudolph, Dale A. Alcazar, Jesus Ameriks, Michael K. Anton, Ana Belen Ao, Hong Bonaventure, Pascal Carruthers, Nicholas I. Chrovian, Christa C. De Angelis, Meri Lord, Brian Rech, Jason C. Wang, Qi Bhattacharya, Anindya Andres, Jose Ignacio Letavic, Michael A. |
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The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50=7.7nM) and 7u (P2X7 IC50=7.7nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers. |
| doi_str_mv | 10.1016/j.bmcl.2015.06.004 |
| format | Article |
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The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50=7.7nM) and 7u (P2X7 IC50=7.7nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.06.004</identifier><identifier>PMID: 26099534</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones ; Animals ; CNS ; Depression ; Half-Life ; Humans ; Microsomes - metabolism ; P2X7 ; Protein Binding ; Purinergic P2X Receptor Antagonists - chemistry ; Purinergic P2X Receptor Antagonists - metabolism ; Purinergic P2X Receptor Antagonists - pharmacokinetics ; Pyrazines - chemistry ; Rats ; Receptors, Purinergic P2X7 - chemistry ; Receptors, Purinergic P2X7 - metabolism ; Structure-Activity Relationship ; Triazoles - chemistry</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-08, Vol.25 (16), p.3157-3163</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-bdc0b796c54276afee00c4215a7a051e6fa60fb9bfe6cf00c54105d069732ccc3</citedby><cites>FETCH-LOGICAL-c426t-bdc0b796c54276afee00c4215a7a051e6fa60fb9bfe6cf00c54105d069732ccc3</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.2015.06.004$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27926,27927,45997</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26099534$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rudolph, Dale A.</creatorcontrib><creatorcontrib>Alcazar, Jesus</creatorcontrib><creatorcontrib>Ameriks, Michael K.</creatorcontrib><creatorcontrib>Anton, Ana Belen</creatorcontrib><creatorcontrib>Ao, Hong</creatorcontrib><creatorcontrib>Bonaventure, Pascal</creatorcontrib><creatorcontrib>Carruthers, Nicholas I.</creatorcontrib><creatorcontrib>Chrovian, Christa C.</creatorcontrib><creatorcontrib>De Angelis, Meri</creatorcontrib><creatorcontrib>Lord, Brian</creatorcontrib><creatorcontrib>Rech, Jason C.</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Bhattacharya, Anindya</creatorcontrib><creatorcontrib>Andres, Jose Ignacio</creatorcontrib><creatorcontrib>Letavic, Michael A.</creatorcontrib><title>Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50=7.7nM) and 7u (P2X7 IC50=7.7nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.</description><subject>5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones</subject><subject>Animals</subject><subject>CNS</subject><subject>Depression</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Microsomes - metabolism</subject><subject>P2X7</subject><subject>Protein Binding</subject><subject>Purinergic P2X Receptor Antagonists - chemistry</subject><subject>Purinergic P2X Receptor Antagonists - metabolism</subject><subject>Purinergic P2X Receptor Antagonists - pharmacokinetics</subject><subject>Pyrazines - chemistry</subject><subject>Rats</subject><subject>Receptors, Purinergic P2X7 - chemistry</subject><subject>Receptors, Purinergic P2X7 - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Triazoles - chemistry</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>eNp9kEFL7DAUhYMoOk_9Ay4eXY4wqTdtklpwI-LTB6IuFASRkKa3zwxtMyapUH-9HUbf0tVdnHM-uB8hRwxSBkyeLNOqM22aARMpyBSAb5EZ45LTnIPYJjMoJdDTkj_tkV8hLAEYB853yV4moSxFzmekv3Xv2CYdxtexTcJQhWjjELFOGJ2LhaS1fR1r7-gzW2QL_hK91R-udc98kVP9shq9_rA9Lean18d0bI_XIN27HkOiPSb32VOR6D7qf663IYYDstPoNuDh190nj38uHy6u6c3d1d-L8xtqeCYjrWoDVVFKI3hWSN0gAkwJE7rQIBjKRktoqrJqUJpmygRnIGqQZZFnxph8n8w33JV3bwOGqDobDLat7tENQTFZ8gIkFzBVs03VeBeCx0atvO20HxUDtfaslmrtWa09K5Bq8jyNfn_xh6rD-v_kW-xUONsUcPry3aJXwVjsDdbWo4mqdvYn_ifkf41g</recordid><startdate>20150815</startdate><enddate>20150815</enddate><creator>Rudolph, Dale A.</creator><creator>Alcazar, Jesus</creator><creator>Ameriks, Michael K.</creator><creator>Anton, Ana Belen</creator><creator>Ao, Hong</creator><creator>Bonaventure, Pascal</creator><creator>Carruthers, Nicholas I.</creator><creator>Chrovian, Christa C.</creator><creator>De Angelis, Meri</creator><creator>Lord, Brian</creator><creator>Rech, Jason C.</creator><creator>Wang, Qi</creator><creator>Bhattacharya, Anindya</creator><creator>Andres, Jose Ignacio</creator><creator>Letavic, Michael A.</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>20150815</creationdate><title>Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists</title><author>Rudolph, Dale A. ; Alcazar, Jesus ; Ameriks, Michael K. ; Anton, Ana Belen ; Ao, Hong ; Bonaventure, Pascal ; Carruthers, Nicholas I. ; Chrovian, Christa C. ; De Angelis, Meri ; Lord, Brian ; Rech, Jason C. ; Wang, Qi ; Bhattacharya, Anindya ; Andres, Jose Ignacio ; Letavic, Michael A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-bdc0b796c54276afee00c4215a7a051e6fa60fb9bfe6cf00c54105d069732ccc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones</topic><topic>Animals</topic><topic>CNS</topic><topic>Depression</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Microsomes - metabolism</topic><topic>P2X7</topic><topic>Protein Binding</topic><topic>Purinergic P2X Receptor Antagonists - chemistry</topic><topic>Purinergic P2X Receptor Antagonists - metabolism</topic><topic>Purinergic P2X Receptor Antagonists - pharmacokinetics</topic><topic>Pyrazines - chemistry</topic><topic>Rats</topic><topic>Receptors, Purinergic P2X7 - chemistry</topic><topic>Receptors, Purinergic P2X7 - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Triazoles - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rudolph, Dale A.</creatorcontrib><creatorcontrib>Alcazar, Jesus</creatorcontrib><creatorcontrib>Ameriks, Michael K.</creatorcontrib><creatorcontrib>Anton, Ana Belen</creatorcontrib><creatorcontrib>Ao, Hong</creatorcontrib><creatorcontrib>Bonaventure, Pascal</creatorcontrib><creatorcontrib>Carruthers, Nicholas I.</creatorcontrib><creatorcontrib>Chrovian, Christa C.</creatorcontrib><creatorcontrib>De Angelis, Meri</creatorcontrib><creatorcontrib>Lord, Brian</creatorcontrib><creatorcontrib>Rech, Jason C.</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Bhattacharya, Anindya</creatorcontrib><creatorcontrib>Andres, Jose Ignacio</creatorcontrib><creatorcontrib>Letavic, Michael A.</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>Rudolph, Dale A.</au><au>Alcazar, Jesus</au><au>Ameriks, Michael K.</au><au>Anton, Ana Belen</au><au>Ao, Hong</au><au>Bonaventure, Pascal</au><au>Carruthers, Nicholas I.</au><au>Chrovian, Christa C.</au><au>De Angelis, Meri</au><au>Lord, Brian</au><au>Rech, Jason C.</au><au>Wang, Qi</au><au>Bhattacharya, Anindya</au><au>Andres, Jose Ignacio</au><au>Letavic, Michael A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-08-15</date><risdate>2015</risdate><volume>25</volume><issue>16</issue><spage>3157</spage><epage>3163</epage><pages>3157-3163</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50=7.7nM) and 7u (P2X7 IC50=7.7nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26099534</pmid><doi>10.1016/j.bmcl.2015.06.004</doi><tpages>7</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2015-08, Vol.25 (16), p.3157-3163 |
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| subjects | 5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones Animals CNS Depression Half-Life Humans Microsomes - metabolism P2X7 Protein Binding Purinergic P2X Receptor Antagonists - chemistry Purinergic P2X Receptor Antagonists - metabolism Purinergic P2X Receptor Antagonists - pharmacokinetics Pyrazines - chemistry Rats Receptors, Purinergic P2X7 - chemistry Receptors, Purinergic P2X7 - metabolism Structure-Activity Relationship Triazoles - chemistry |
| title | Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists |
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