Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors
[Display omitted] •Novel PDE10 inhibitors.•Optimization supported by X-ray crystal structure analysis and molecular modeling.•Potent, selective, and brain penetrant.•Improved PK profile (rat): lower clearance in vivo and decreased volume of distribution (compared to WEB-3). Herein we report the disc...
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| Veröffentlicht in: | Bioorg. Med. Chem. Lett 2019-02, Vol.29 (3), p.406-412 |
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| container_title | Bioorg. Med. Chem. Lett |
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| creator | Geneste, Hervé Drescher, Karla Jakob, Clarissa Laplanche, Loïc Ochse, Michael Torrent, Maricel |
| description | [Display omitted]
•Novel PDE10 inhibitors.•Optimization supported by X-ray crystal structure analysis and molecular modeling.•Potent, selective, and brain penetrant.•Improved PK profile (rat): lower clearance in vivo and decreased volume of distribution (compared to WEB-3).
Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3. |
| doi_str_mv | 10.1016/j.bmcl.2018.12.029 |
| format | Article |
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•Novel PDE10 inhibitors.•Optimization supported by X-ray crystal structure analysis and molecular modeling.•Potent, selective, and brain penetrant.•Improved PK profile (rat): lower clearance in vivo and decreased volume of distribution (compared to WEB-3).
Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2018.12.029</identifier><identifier>PMID: 30587449</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Dose-Response Relationship, Drug ; Heterocyclic Compounds, 2-Ring - chemical synthesis ; Heterocyclic Compounds, 2-Ring - chemistry ; Heterocyclic Compounds, 2-Ring - pharmacology ; Humans ; Models, Molecular ; Molecular Structure ; PDE10A ; Phosphodiesterase ; Phosphodiesterase Inhibitors - chemical synthesis ; Phosphodiesterase Inhibitors - chemistry ; Phosphodiesterase Inhibitors - pharmacology ; Phosphoric Diester Hydrolases - metabolism ; Pyrazines - chemical synthesis ; Pyrazines - chemistry ; Pyrazines - pharmacology ; Rats ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - chemistry ; Thiazoles - pharmacology ; WEB-3</subject><ispartof>Bioorg. Med. Chem. Lett, 2019-02, Vol.29 (3), p.406-412</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-8cab67f2b8d67d14b2fd87375d2ef79d26da4853093ffdce6420fd2e0d961313</citedby><cites>FETCH-LOGICAL-c427t-8cab67f2b8d67d14b2fd87375d2ef79d26da4853093ffdce6420fd2e0d961313</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.2018.12.029$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30587449$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1557274$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Geneste, Hervé</creatorcontrib><creatorcontrib>Drescher, Karla</creatorcontrib><creatorcontrib>Jakob, Clarissa</creatorcontrib><creatorcontrib>Laplanche, Loïc</creatorcontrib><creatorcontrib>Ochse, Michael</creatorcontrib><creatorcontrib>Torrent, Maricel</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors</title><title>Bioorg. Med. Chem. Lett</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
•Novel PDE10 inhibitors.•Optimization supported by X-ray crystal structure analysis and molecular modeling.•Potent, selective, and brain penetrant.•Improved PK profile (rat): lower clearance in vivo and decreased volume of distribution (compared to WEB-3).
Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.</description><subject>Animals</subject><subject>Dose-Response Relationship, Drug</subject><subject>Heterocyclic Compounds, 2-Ring - chemical synthesis</subject><subject>Heterocyclic Compounds, 2-Ring - chemistry</subject><subject>Heterocyclic Compounds, 2-Ring - pharmacology</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>PDE10A</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase Inhibitors - chemical synthesis</subject><subject>Phosphodiesterase Inhibitors - chemistry</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phosphoric Diester Hydrolases - metabolism</subject><subject>Pyrazines - chemical synthesis</subject><subject>Pyrazines - chemistry</subject><subject>Pyrazines - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><subject>WEB-3</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFq3DAQhkVoSTZpX6CHYnrKYe2OZFmyoZcQ0rQQ0ksOvQlZGrNavJIraRf69pXZtMcehjnMNz8_HyEfKDQUqPi8b8aDmRsGtG8oa4ANF2RDueB1y6F7QzYwCKj7gf-8Itcp7QEoB84vyVULXS85Hzbk-TmccN5WS8jo87ZKOKPJ7oTbSntbjVE7Xy3oMUftc7XsQipjHaaMUSesKNxVzu_c6HKI6R15O-k54fvXfUNevj683H-rn348fr-_e6oNZzLXvdGjkBMbeyukpXxkk-1lKzvLcJKDZcJq3nctDO00WYOCM5jKDewgaEvbG_LpHBtSdioZl9HsTPC-dFe06ySTvEC3Z2iJ4dexFFYHlwzOs_YYjkkxKiiIlrI1j51RE0NKESe1RHfQ8beioFbXaq9W12p1rShTxXV5-viafxwPaP-9_JVbgC9nAIuJk8O4NkVv0Lq4FrXB_S__D-YZj3M</recordid><startdate>20190201</startdate><enddate>20190201</enddate><creator>Geneste, Hervé</creator><creator>Drescher, Karla</creator><creator>Jakob, Clarissa</creator><creator>Laplanche, Loïc</creator><creator>Ochse, Michael</creator><creator>Torrent, Maricel</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><scope>OTOTI</scope></search><sort><creationdate>20190201</creationdate><title>Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors</title><author>Geneste, Hervé ; Drescher, Karla ; Jakob, Clarissa ; Laplanche, Loïc ; Ochse, Michael ; Torrent, Maricel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-8cab67f2b8d67d14b2fd87375d2ef79d26da4853093ffdce6420fd2e0d961313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Dose-Response Relationship, Drug</topic><topic>Heterocyclic Compounds, 2-Ring - chemical synthesis</topic><topic>Heterocyclic Compounds, 2-Ring - chemistry</topic><topic>Heterocyclic Compounds, 2-Ring - pharmacology</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>PDE10A</topic><topic>Phosphodiesterase</topic><topic>Phosphodiesterase Inhibitors - chemical synthesis</topic><topic>Phosphodiesterase Inhibitors - chemistry</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phosphoric Diester Hydrolases - metabolism</topic><topic>Pyrazines - chemical synthesis</topic><topic>Pyrazines - chemistry</topic><topic>Pyrazines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - pharmacology</topic><topic>WEB-3</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geneste, Hervé</creatorcontrib><creatorcontrib>Drescher, Karla</creatorcontrib><creatorcontrib>Jakob, Clarissa</creatorcontrib><creatorcontrib>Laplanche, Loïc</creatorcontrib><creatorcontrib>Ochse, Michael</creatorcontrib><creatorcontrib>Torrent, Maricel</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</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><collection>OSTI.GOV</collection><jtitle>Bioorg. Med. Chem. Lett</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geneste, Hervé</au><au>Drescher, Karla</au><au>Jakob, Clarissa</au><au>Laplanche, Loïc</au><au>Ochse, Michael</au><au>Torrent, Maricel</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors</atitle><jtitle>Bioorg. Med. Chem. Lett</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2019-02-01</date><risdate>2019</risdate><volume>29</volume><issue>3</issue><spage>406</spage><epage>412</epage><pages>406-412</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
•Novel PDE10 inhibitors.•Optimization supported by X-ray crystal structure analysis and molecular modeling.•Potent, selective, and brain penetrant.•Improved PK profile (rat): lower clearance in vivo and decreased volume of distribution (compared to WEB-3).
Herein we report the discovery of a novel series of phosphodiesterase 10A inhibitors. Optimization of a HTS hit (17) resulted in potent, selective, and brain penetrant 23 and 26; both exhibited much lower clearance in vivo and decreased volume of distribution (rat PK) and have thus the potential to inhibit the PDE10A target in vivo at a lower efficacious dose than the reference compound WEB-3.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30587449</pmid><doi>10.1016/j.bmcl.2018.12.029</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Dose-Response Relationship, Drug Heterocyclic Compounds, 2-Ring - chemical synthesis Heterocyclic Compounds, 2-Ring - chemistry Heterocyclic Compounds, 2-Ring - pharmacology Humans Models, Molecular Molecular Structure PDE10A Phosphodiesterase Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - metabolism Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - pharmacology Rats Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacology WEB-3 |
| title | Novel, potent, selective, and brain penetrant phosphodiesterase 10A inhibitors |
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