Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors
[Display omitted] Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (4), p.919-924 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Yang, Hao Murigi, Francis N. Wang, Zhijian Li, Junfeng Jin, Hongjun Tu, Zhude |
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Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52±0.18, 2.86±0.10, and 3.73±0.60nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain. |
| doi_str_mv | 10.1016/j.bmcl.2014.12.054 |
| format | Article |
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Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52±0.18, 2.86±0.10, and 3.73±0.60nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.12.054</identifier><identifier>PMID: 25592707</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Benzimidazole analogues ; Benzimidazoles - pharmacology ; Cinnoline analogues ; Heterocyclic Compounds, 2-Ring - pharmacology ; Humans ; In Vitro Techniques ; PET ; Phosphodiesterase 10A ; Phosphodiesterase Inhibitors - pharmacology ; Phosphoric Diester Hydrolases - drug effects</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (4), p.919-924</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><rights>2014 Elsevier Ltd. All rights reserved. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c558t-fa6d9c4f35141a393683eb6073ee3fec3a173a93ea6a06ded15f3db564e9ca403</citedby><cites>FETCH-LOGICAL-c558t-fa6d9c4f35141a393683eb6073ee3fec3a173a93ea6a06ded15f3db564e9ca403</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.2014.12.054$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25592707$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Hao</creatorcontrib><creatorcontrib>Murigi, Francis N.</creatorcontrib><creatorcontrib>Wang, Zhijian</creatorcontrib><creatorcontrib>Li, Junfeng</creatorcontrib><creatorcontrib>Jin, Hongjun</creatorcontrib><creatorcontrib>Tu, Zhude</creatorcontrib><title>Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52±0.18, 2.86±0.10, and 3.73±0.60nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.</description><subject>Benzimidazole analogues</subject><subject>Benzimidazoles - pharmacology</subject><subject>Cinnoline analogues</subject><subject>Heterocyclic Compounds, 2-Ring - pharmacology</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>PET</subject><subject>Phosphodiesterase 10A</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phosphoric Diester Hydrolases - drug effects</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>eNqNkc2KFDEUhYMoTtv6Ai6klm6qTCo_1QUiDMP4AwMuVHAXUsmtqdtUJW2Sbph-etP2OOhGXIRA8t2PnBxCXjLaMMrUm20zLHZuWspEw9qGSvGIrJhQouaCysdkRXtF600vvl-QZyltaQGpEE_JRStl33a0W5H85c7nCRKmynhXoa8OmGOo7GSisRkiHk3G4KswVha9DzN6-IUO4I-4oDPHMJ9OzBxu91A0qdpNIZXlEFIxmAQVo5fFPeGAOcT0nDwZzZzgxf2-Jt_eX3-9-ljffP7w6eryprZSbnI9GuV6K0YumWCG91xtOAyKdhyAj2C5YR03PQejDFUOHJMjd4NUAnprBOVr8u7s3e2HBZwFn6OZ9S7iYuKdDgb13zceJ30bDlrwtqh5Eby-F8Two4TLesFkYZ6Nh7BPmilFBe26Xv4HKlshVFtirEl7Rm0MKUUYH17EqD41q7f61Kw-NatZq0uzZejVn1keRn5XWYC3ZwDKjx4Qok4WwVtwGMFm7QL-y_8T4vO4kQ</recordid><startdate>20150215</startdate><enddate>20150215</enddate><creator>Yang, Hao</creator><creator>Murigi, Francis N.</creator><creator>Wang, Zhijian</creator><creator>Li, Junfeng</creator><creator>Jin, Hongjun</creator><creator>Tu, Zhude</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20150215</creationdate><title>Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors</title><author>Yang, Hao ; Murigi, Francis N. ; Wang, Zhijian ; Li, Junfeng ; Jin, Hongjun ; Tu, Zhude</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c558t-fa6d9c4f35141a393683eb6073ee3fec3a173a93ea6a06ded15f3db564e9ca403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Benzimidazole analogues</topic><topic>Benzimidazoles - pharmacology</topic><topic>Cinnoline analogues</topic><topic>Heterocyclic Compounds, 2-Ring - pharmacology</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>PET</topic><topic>Phosphodiesterase 10A</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phosphoric Diester Hydrolases - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Hao</creatorcontrib><creatorcontrib>Murigi, Francis N.</creatorcontrib><creatorcontrib>Wang, Zhijian</creatorcontrib><creatorcontrib>Li, Junfeng</creatorcontrib><creatorcontrib>Jin, Hongjun</creatorcontrib><creatorcontrib>Tu, Zhude</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Hao</au><au>Murigi, Francis N.</au><au>Wang, Zhijian</au><au>Li, Junfeng</au><au>Jin, Hongjun</au><au>Tu, Zhude</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-02-15</date><risdate>2015</risdate><volume>25</volume><issue>4</issue><spage>919</spage><epage>924</epage><pages>919-924</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Fifteen cinnoline analogues and six benzimidazole phosphodiesterase 10A (PDE10A) inhibitors were synthesized as potential PET radiopharmaceuticals and their in vitro activity as PDE10A inhibitors was determined. Nine out of twenty-one compounds were potent inhibitors of PDE10A with IC50 values ranging from 1.5 to 18.6nM. Notably, the IC50 values of compounds 26a, 26b, and 33c were 1.52±0.18, 2.86±0.10, and 3.73±0.60nM, respectively; these three compounds also showed high in vitro selectivity (>1000-fold) for PDE10A over PDE 3A/3B, PDE4A/4B. The high potency and selectivity of these three compounds suggests that they could be radiolabeled with PET radionuclides for further evaluation of their in vivo pharmacological behavior and ability to quantify PDE10A in the brain.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25592707</pmid><doi>10.1016/j.bmcl.2014.12.054</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2015-02, Vol.25 (4), p.919-924 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Benzimidazole analogues Benzimidazoles - pharmacology Cinnoline analogues Heterocyclic Compounds, 2-Ring - pharmacology Humans In Vitro Techniques PET Phosphodiesterase 10A Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - drug effects |
| title | Synthesis and in vitro characterization of cinnoline and benzimidazole analogues as phosphodiesterase 10A inhibitors |
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