4‑Methyl-6,7-dihydro‑4H‑triazolo[4,5‑c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate
The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, met...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-06, Vol.60 (11), p.4559-4572 |
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| container_title | Journal of medicinal chemistry |
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| creator | Letavic, Michael A Savall, Brad M Allison, Brett D Aluisio, Leah Andres, Jose Ignacio De Angelis, Meri Ao, Hong Beauchamp, Derek A Bonaventure, Pascal Bryant, Stewart Carruthers, Nicholas I Ceusters, Marc Coe, Kevin J Dvorak, Curt A Fraser, Ian C Gelin, Christine F Koudriakova, Tatiana Liang, Jimmy Lord, Brian Lovenberg, Timothy W Otieno, Monicah A Schoetens, Freddy Swanson, Devin M Wang, Qi Wickenden, Alan D Bhattacharya, Anindya |
| description | The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00408 |
| format | Article |
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Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b00408</identifier><identifier>PMID: 28493698</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Biological Availability ; Humans ; Purinergic P2X Receptor Antagonists - pharmacokinetics ; Purinergic P2X Receptor Antagonists - pharmacology ; Pyridines - pharmacology ; Receptors, Purinergic P2X7 - drug effects</subject><ispartof>Journal of medicinal chemistry, 2017-06, Vol.60 (11), p.4559-4572</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-7503-0189</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00408$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00408$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28493698$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Letavic, Michael A</creatorcontrib><creatorcontrib>Savall, Brad M</creatorcontrib><creatorcontrib>Allison, Brett D</creatorcontrib><creatorcontrib>Aluisio, Leah</creatorcontrib><creatorcontrib>Andres, Jose Ignacio</creatorcontrib><creatorcontrib>De Angelis, Meri</creatorcontrib><creatorcontrib>Ao, Hong</creatorcontrib><creatorcontrib>Beauchamp, Derek A</creatorcontrib><creatorcontrib>Bonaventure, Pascal</creatorcontrib><creatorcontrib>Bryant, Stewart</creatorcontrib><creatorcontrib>Carruthers, Nicholas I</creatorcontrib><creatorcontrib>Ceusters, Marc</creatorcontrib><creatorcontrib>Coe, Kevin J</creatorcontrib><creatorcontrib>Dvorak, Curt A</creatorcontrib><creatorcontrib>Fraser, Ian C</creatorcontrib><creatorcontrib>Gelin, Christine F</creatorcontrib><creatorcontrib>Koudriakova, Tatiana</creatorcontrib><creatorcontrib>Liang, Jimmy</creatorcontrib><creatorcontrib>Lord, Brian</creatorcontrib><creatorcontrib>Lovenberg, Timothy W</creatorcontrib><creatorcontrib>Otieno, Monicah A</creatorcontrib><creatorcontrib>Schoetens, Freddy</creatorcontrib><creatorcontrib>Swanson, Devin M</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Wickenden, Alan D</creatorcontrib><creatorcontrib>Bhattacharya, Anindya</creatorcontrib><title>4‑Methyl-6,7-dihydro‑4H‑triazolo[4,5‑c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.</description><subject>Animals</subject><subject>Biological Availability</subject><subject>Humans</subject><subject>Purinergic P2X Receptor Antagonists - pharmacokinetics</subject><subject>Purinergic P2X Receptor Antagonists - pharmacology</subject><subject>Pyridines - pharmacology</subject><subject>Receptors, Purinergic P2X7 - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kcFu1DAQhi0EokvhDRDykUOzjO1s4nArq5ZW2qorBBISQpHXHjdekjjY3sP2xCvwIDxBbzwKT4KhC5cZza__H43mI-Q5gzkDzl4pHefbAY3ucJjXG4AS5AMyYwsORSmhfEhmAJwXvOLiiDyJcQsAgnHxmBxxWTaiauSM3JW_vn2_wtTt-6I6qQvjur0JPovlRS4pOHXre_-pPFnkUX_--WPaB2fciMUbFdHQNf9Y03eocUo-0NMxqRs_upjia3o9JTe4W5WcH6m3dN2pMCjtv-R0cpqug58wJIeRrlDlnTc0eZo6pJcGx-Ss0_-zii57N2ahp0s1GmdUwqfkkVV9xGeHfkw-nJ-9X14Uq-u3l8vTVaF4I1NhsGG6tMxWsDF8UwuBvDZCKmBYGVlxbpFpa7gG5FbaSmjdSKMruVAVWBTH5OX93in4rzuMqR1c1Nj3akS_iy2TTcMY5JKtLw7W3SazaafgBhX27b-HZwPcGzK-dut3YcyXtwzaP0zbv-KBaXtgKn4D1Aqdfw</recordid><startdate>20170608</startdate><enddate>20170608</enddate><creator>Letavic, Michael A</creator><creator>Savall, Brad M</creator><creator>Allison, Brett D</creator><creator>Aluisio, Leah</creator><creator>Andres, Jose Ignacio</creator><creator>De Angelis, Meri</creator><creator>Ao, Hong</creator><creator>Beauchamp, Derek A</creator><creator>Bonaventure, Pascal</creator><creator>Bryant, Stewart</creator><creator>Carruthers, Nicholas I</creator><creator>Ceusters, Marc</creator><creator>Coe, Kevin J</creator><creator>Dvorak, Curt A</creator><creator>Fraser, Ian C</creator><creator>Gelin, Christine F</creator><creator>Koudriakova, Tatiana</creator><creator>Liang, Jimmy</creator><creator>Lord, Brian</creator><creator>Lovenberg, Timothy W</creator><creator>Otieno, Monicah A</creator><creator>Schoetens, Freddy</creator><creator>Swanson, Devin M</creator><creator>Wang, Qi</creator><creator>Wickenden, Alan D</creator><creator>Bhattacharya, Anindya</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>7X8</scope><orcidid>https://orcid.org/0000-0002-7503-0189</orcidid></search><sort><creationdate>20170608</creationdate><title>4‑Methyl-6,7-dihydro‑4H‑triazolo[4,5‑c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate</title><author>Letavic, Michael A ; Savall, Brad M ; Allison, Brett D ; Aluisio, Leah ; Andres, Jose Ignacio ; De Angelis, Meri ; Ao, Hong ; Beauchamp, Derek A ; Bonaventure, Pascal ; Bryant, Stewart ; Carruthers, Nicholas I ; Ceusters, Marc ; Coe, Kevin J ; Dvorak, Curt A ; Fraser, Ian C ; Gelin, Christine F ; Koudriakova, Tatiana ; Liang, Jimmy ; Lord, Brian ; Lovenberg, Timothy W ; Otieno, Monicah A ; Schoetens, Freddy ; Swanson, Devin M ; Wang, Qi ; Wickenden, Alan D ; Bhattacharya, Anindya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a298t-de91c4f1f60bd2b733e27d38a01e6d8622fe1cfd2c0e2f8f63cc98dc685a60fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Biological Availability</topic><topic>Humans</topic><topic>Purinergic P2X Receptor Antagonists - pharmacokinetics</topic><topic>Purinergic P2X Receptor Antagonists - pharmacology</topic><topic>Pyridines - pharmacology</topic><topic>Receptors, Purinergic P2X7 - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Letavic, Michael A</creatorcontrib><creatorcontrib>Savall, Brad M</creatorcontrib><creatorcontrib>Allison, Brett D</creatorcontrib><creatorcontrib>Aluisio, Leah</creatorcontrib><creatorcontrib>Andres, Jose Ignacio</creatorcontrib><creatorcontrib>De Angelis, Meri</creatorcontrib><creatorcontrib>Ao, Hong</creatorcontrib><creatorcontrib>Beauchamp, Derek A</creatorcontrib><creatorcontrib>Bonaventure, Pascal</creatorcontrib><creatorcontrib>Bryant, Stewart</creatorcontrib><creatorcontrib>Carruthers, Nicholas I</creatorcontrib><creatorcontrib>Ceusters, Marc</creatorcontrib><creatorcontrib>Coe, Kevin J</creatorcontrib><creatorcontrib>Dvorak, Curt A</creatorcontrib><creatorcontrib>Fraser, Ian C</creatorcontrib><creatorcontrib>Gelin, Christine F</creatorcontrib><creatorcontrib>Koudriakova, Tatiana</creatorcontrib><creatorcontrib>Liang, Jimmy</creatorcontrib><creatorcontrib>Lord, Brian</creatorcontrib><creatorcontrib>Lovenberg, Timothy W</creatorcontrib><creatorcontrib>Otieno, Monicah A</creatorcontrib><creatorcontrib>Schoetens, Freddy</creatorcontrib><creatorcontrib>Swanson, Devin M</creatorcontrib><creatorcontrib>Wang, Qi</creatorcontrib><creatorcontrib>Wickenden, Alan D</creatorcontrib><creatorcontrib>Bhattacharya, Anindya</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Letavic, Michael A</au><au>Savall, Brad M</au><au>Allison, Brett D</au><au>Aluisio, Leah</au><au>Andres, Jose Ignacio</au><au>De Angelis, Meri</au><au>Ao, Hong</au><au>Beauchamp, Derek A</au><au>Bonaventure, Pascal</au><au>Bryant, Stewart</au><au>Carruthers, Nicholas I</au><au>Ceusters, Marc</au><au>Coe, Kevin J</au><au>Dvorak, Curt A</au><au>Fraser, Ian C</au><au>Gelin, Christine F</au><au>Koudriakova, Tatiana</au><au>Liang, Jimmy</au><au>Lord, Brian</au><au>Lovenberg, Timothy W</au><au>Otieno, Monicah A</au><au>Schoetens, Freddy</au><au>Swanson, Devin M</au><au>Wang, Qi</au><au>Wickenden, Alan D</au><au>Bhattacharya, Anindya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>4‑Methyl-6,7-dihydro‑4H‑triazolo[4,5‑c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-06-08</date><risdate>2017</risdate><volume>60</volume><issue>11</issue><spage>4559</spage><epage>4572</epage><pages>4559-4572</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28493698</pmid><doi>10.1021/acs.jmedchem.7b00408</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-7503-0189</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2017-06, Vol.60 (11), p.4559-4572 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Biological Availability Humans Purinergic P2X Receptor Antagonists - pharmacokinetics Purinergic P2X Receptor Antagonists - pharmacology Pyridines - pharmacology Receptors, Purinergic P2X7 - drug effects |
| title | 4‑Methyl-6,7-dihydro‑4H‑triazolo[4,5‑c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate |
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