Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3‑a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain
Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC50 = 9 nM; rat P2X7 IC50 = 42 nM) achieved 80% receptor occupancy for 6 h when dosed oral...
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| Veröffentlicht in: | ACS chemical neuroscience 2016-04, Vol.7 (4), p.490-497 |
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| container_title | ACS chemical neuroscience |
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| creator | Chrovian, Christa C Soyode-Johnson, Akinola Ao, Hong Bacani, Genesis M Carruthers, Nicholas I Lord, Brian Nguyen, Leslie Rech, Jason C Wang, Qi Bhattacharya, Anindya Letavic, Michael A |
| description | Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC50 = 9 nM; rat P2X7 IC50 = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure–activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included. |
| doi_str_mv | 10.1021/acschemneuro.5b00303 |
| format | Article |
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Neurosci</addtitle><description>Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC50 = 9 nM; rat P2X7 IC50 = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure–activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included.</description><subject>Animals</subject><subject>Autoradiography</subject><subject>Binding, Competitive - drug effects</subject><subject>Brain - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Inhibitory Concentration 50</subject><subject>Protein Binding - drug effects</subject><subject>Purinergic P2X Receptor Antagonists - chemistry</subject><subject>Purinergic P2X Receptor Antagonists - pharmacology</subject><subject>Pyrazines - chemistry</subject><subject>Pyrazines - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><issn>1948-7193</issn><issn>1948-7193</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtKAzEUhoMoXqpvIJKli44mk8xtqfUKouIFBJEhk5y2kZmkJhmlrvQRfEWfxJFWceXqnMX__YfzIbRJyQ4lMd0V0ssxNAZaZ3eSihBG2AJapQXPo4wWbPHPvoLWvH8kJC1Ini6jlTjNkphStorez-0z1PhyDGZaR9dt5YMObQCFk34aHejxVDkb3dN-3OcPwWnxamt7z_vs8-1DPEymTrxqA_gyvsvwngliZI32weMXHcb4ylatD_hGuBEEfGhGYgQNmIC1wVci4H0ntFlHS0NRe9iYzx66PTq8GZxEZxfHp4O9s0gwnoeICihSqSiVUmYJFHHOE56DollKFGOcDgkTiSwKUsks50XKmEoVSypJc1kNFeuh7VnvxNmnFnwoG-0l1LUwYFtf0ixnjGW809JDfBaVznrvYFhOnG6Em5aUlN_yy7_yy7n8DtuaX2irBtQv9GO7C5BZoMPLR9s60z38f-cXv4SVQg</recordid><startdate>20160420</startdate><enddate>20160420</enddate><creator>Chrovian, Christa C</creator><creator>Soyode-Johnson, Akinola</creator><creator>Ao, Hong</creator><creator>Bacani, Genesis M</creator><creator>Carruthers, Nicholas I</creator><creator>Lord, Brian</creator><creator>Nguyen, Leslie</creator><creator>Rech, Jason C</creator><creator>Wang, Qi</creator><creator>Bhattacharya, Anindya</creator><creator>Letavic, Michael A</creator><general>American Chemical Society</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>20160420</creationdate><title>Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3‑a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain</title><author>Chrovian, Christa C ; Soyode-Johnson, Akinola ; Ao, Hong ; Bacani, Genesis M ; Carruthers, Nicholas I ; Lord, Brian ; Nguyen, Leslie ; Rech, Jason C ; Wang, Qi ; Bhattacharya, Anindya ; Letavic, Michael A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-1ae96cd11ccc75e9284548ed1760d3341f03a5c990bc7849633d6d35bc18cbfd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Autoradiography</topic><topic>Binding, Competitive - drug effects</topic><topic>Brain - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Inhibitory Concentration 50</topic><topic>Protein Binding - drug effects</topic><topic>Purinergic P2X Receptor Antagonists - chemistry</topic><topic>Purinergic P2X Receptor Antagonists - pharmacology</topic><topic>Pyrazines - chemistry</topic><topic>Pyrazines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chrovian, Christa C</creatorcontrib><creatorcontrib>Soyode-Johnson, Akinola</creatorcontrib><creatorcontrib>Ao, Hong</creatorcontrib><creatorcontrib>Bacani, Genesis M</creatorcontrib><creatorcontrib>Carruthers, Nicholas I</creatorcontrib><creatorcontrib>Lord, Brian</creatorcontrib><creatorcontrib>Nguyen, Leslie</creatorcontrib><creatorcontrib>Rech, Jason C</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Bhattacharya, Anindya</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>ACS chemical neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chrovian, Christa C</au><au>Soyode-Johnson, Akinola</au><au>Ao, Hong</au><au>Bacani, Genesis M</au><au>Carruthers, Nicholas I</au><au>Lord, Brian</au><au>Nguyen, Leslie</au><au>Rech, Jason C</au><au>Wang, Qi</au><au>Bhattacharya, Anindya</au><au>Letavic, Michael A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3‑a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain</atitle><jtitle>ACS chemical neuroscience</jtitle><addtitle>ACS Chem. 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| subjects | Animals Autoradiography Binding, Competitive - drug effects Brain - drug effects Dose-Response Relationship, Drug Humans In Vitro Techniques Inhibitory Concentration 50 Protein Binding - drug effects Purinergic P2X Receptor Antagonists - chemistry Purinergic P2X Receptor Antagonists - pharmacology Pyrazines - chemistry Pyrazines - pharmacology Rats Structure-Activity Relationship |
| title | Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3‑a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain |
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