1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists
[Display omitted] A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry 2016-04, Vol.24 (8), p.1619-1636 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1636 |
|---|---|
| container_issue | 8 |
| container_start_page | 1619 |
| container_title | Bioorganic & medicinal chemistry |
| container_volume | 24 |
| creator | Micheli, Fabrizio Bernardelli, Andrea Bianchi, Federica Braggio, Simone Castelletti, Laura Cavallini, Palmina Cavanni, Paolo Cremonesi, Susanna Cin, Michele Dal Feriani, Aldo Oliosi, Beatrice Semeraro, Teresa Tarsi, Luca Tomelleri, Silvia Wong, Andrea Visentini, Filippo Zonzini, Laura Heidbreder, Christian |
| description | [Display omitted]
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule. |
| doi_str_mv | 10.1016/j.bmc.2016.02.031 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1790945054</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0968089616301225</els_id><sourcerecordid>1776629807</sourcerecordid><originalsourceid>FETCH-LOGICAL-c386t-ce1cdb765708333154816b7d299759f62700c5a9df57ec561c69d79e26a275c43</originalsourceid><addsrcrecordid>eNqNkUtv1DAURi0EotPCD2CDvGQxCX7EdgyrqqWAVIlNWSFkOfYNeJTEwfYMGn49rqawRKzuQ-d-i3sQekFJSwmVr3ftMLuW1bYlrCWcPkIb2smu4VzTx2hDtOwb0mt5hs5z3hFCWKfpU3TGpBa0190GHeiWbbvmLgX7K07HCUdX7PejT3E9phSn-IVteTN8PU2Q3-BLvMBPnCEFyDiOeI0FloLt4utyAlfCAbCPq53DAvia4wQO1hJTRYr9FpeQS36Gnox2yvD8oV6gzzfv7q4-NLef3n-8urxtHO9laRxQ5wclhSI955yKrqdyUJ5prYQeJVOEOGG1H4UCJyR1UnulgUnLlHAdv0CvTrlrij_2kIuZQ3YwTXaBuM-GKk10J4j4H1RJyXRPVEXpCXUp5pxgNGsKs01HQ4m5N2N2ppox92YMYaaaqTcvH-L3wwz-78UfFRV4ewKg_uMQIJnsAiwOfKgfLMbH8I_43zNGnak</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1776629807</pqid></control><display><type>article</type><title>1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Micheli, Fabrizio ; Bernardelli, Andrea ; Bianchi, Federica ; Braggio, Simone ; Castelletti, Laura ; Cavallini, Palmina ; Cavanni, Paolo ; Cremonesi, Susanna ; Cin, Michele Dal ; Feriani, Aldo ; Oliosi, Beatrice ; Semeraro, Teresa ; Tarsi, Luca ; Tomelleri, Silvia ; Wong, Andrea ; Visentini, Filippo ; Zonzini, Laura ; Heidbreder, Christian</creator><creatorcontrib>Micheli, Fabrizio ; Bernardelli, Andrea ; Bianchi, Federica ; Braggio, Simone ; Castelletti, Laura ; Cavallini, Palmina ; Cavanni, Paolo ; Cremonesi, Susanna ; Cin, Michele Dal ; Feriani, Aldo ; Oliosi, Beatrice ; Semeraro, Teresa ; Tarsi, Luca ; Tomelleri, Silvia ; Wong, Andrea ; Visentini, Filippo ; Zonzini, Laura ; Heidbreder, Christian</creatorcontrib><description>[Display omitted]
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2016.02.031</identifier><identifier>PMID: 26951894</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Addiction ; Animals ; Antagonist ; Binding, Competitive - drug effects ; CHO Cells ; Cricetulus ; DA D3 receptor ; Dopamine ; Dose-Response Relationship, Drug ; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors ; HEK293 Cells ; Humans ; Models, Molecular ; Molecular Structure ; Neuroscience ; Pyrroles - chemical synthesis ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Receptors, Dopamine D3 - antagonists & inhibitors ; Structure-Activity Relationship ; Triazoles - chemical synthesis ; Triazoles - chemistry ; Triazoles - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry, 2016-04, Vol.24 (8), p.1619-1636</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-ce1cdb765708333154816b7d299759f62700c5a9df57ec561c69d79e26a275c43</citedby><cites>FETCH-LOGICAL-c386t-ce1cdb765708333154816b7d299759f62700c5a9df57ec561c69d79e26a275c43</cites><orcidid>0000-0002-1871-5288</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2016.02.031$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26951894$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Micheli, Fabrizio</creatorcontrib><creatorcontrib>Bernardelli, Andrea</creatorcontrib><creatorcontrib>Bianchi, Federica</creatorcontrib><creatorcontrib>Braggio, Simone</creatorcontrib><creatorcontrib>Castelletti, Laura</creatorcontrib><creatorcontrib>Cavallini, Palmina</creatorcontrib><creatorcontrib>Cavanni, Paolo</creatorcontrib><creatorcontrib>Cremonesi, Susanna</creatorcontrib><creatorcontrib>Cin, Michele Dal</creatorcontrib><creatorcontrib>Feriani, Aldo</creatorcontrib><creatorcontrib>Oliosi, Beatrice</creatorcontrib><creatorcontrib>Semeraro, Teresa</creatorcontrib><creatorcontrib>Tarsi, Luca</creatorcontrib><creatorcontrib>Tomelleri, Silvia</creatorcontrib><creatorcontrib>Wong, Andrea</creatorcontrib><creatorcontrib>Visentini, Filippo</creatorcontrib><creatorcontrib>Zonzini, Laura</creatorcontrib><creatorcontrib>Heidbreder, Christian</creatorcontrib><title>1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.</description><subject>Addiction</subject><subject>Animals</subject><subject>Antagonist</subject><subject>Binding, Competitive - drug effects</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>DA D3 receptor</subject><subject>Dopamine</subject><subject>Dose-Response Relationship, Drug</subject><subject>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Neuroscience</subject><subject>Pyrroles - chemical synthesis</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Receptors, Dopamine D3 - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Triazoles - chemical synthesis</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacology</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtv1DAURi0EotPCD2CDvGQxCX7EdgyrqqWAVIlNWSFkOfYNeJTEwfYMGn49rqawRKzuQ-d-i3sQekFJSwmVr3ftMLuW1bYlrCWcPkIb2smu4VzTx2hDtOwb0mt5hs5z3hFCWKfpU3TGpBa0190GHeiWbbvmLgX7K07HCUdX7PejT3E9phSn-IVteTN8PU2Q3-BLvMBPnCEFyDiOeI0FloLt4utyAlfCAbCPq53DAvia4wQO1hJTRYr9FpeQS36Gnox2yvD8oV6gzzfv7q4-NLef3n-8urxtHO9laRxQ5wclhSI955yKrqdyUJ5prYQeJVOEOGG1H4UCJyR1UnulgUnLlHAdv0CvTrlrij_2kIuZQ3YwTXaBuM-GKk10J4j4H1RJyXRPVEXpCXUp5pxgNGsKs01HQ4m5N2N2ppox92YMYaaaqTcvH-L3wwz-78UfFRV4ewKg_uMQIJnsAiwOfKgfLMbH8I_43zNGnak</recordid><startdate>20160415</startdate><enddate>20160415</enddate><creator>Micheli, Fabrizio</creator><creator>Bernardelli, Andrea</creator><creator>Bianchi, Federica</creator><creator>Braggio, Simone</creator><creator>Castelletti, Laura</creator><creator>Cavallini, Palmina</creator><creator>Cavanni, Paolo</creator><creator>Cremonesi, Susanna</creator><creator>Cin, Michele Dal</creator><creator>Feriani, Aldo</creator><creator>Oliosi, Beatrice</creator><creator>Semeraro, Teresa</creator><creator>Tarsi, Luca</creator><creator>Tomelleri, Silvia</creator><creator>Wong, Andrea</creator><creator>Visentini, Filippo</creator><creator>Zonzini, Laura</creator><creator>Heidbreder, Christian</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><orcidid>https://orcid.org/0000-0002-1871-5288</orcidid></search><sort><creationdate>20160415</creationdate><title>1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists</title><author>Micheli, Fabrizio ; Bernardelli, Andrea ; Bianchi, Federica ; Braggio, Simone ; Castelletti, Laura ; Cavallini, Palmina ; Cavanni, Paolo ; Cremonesi, Susanna ; Cin, Michele Dal ; Feriani, Aldo ; Oliosi, Beatrice ; Semeraro, Teresa ; Tarsi, Luca ; Tomelleri, Silvia ; Wong, Andrea ; Visentini, Filippo ; Zonzini, Laura ; Heidbreder, Christian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-ce1cdb765708333154816b7d299759f62700c5a9df57ec561c69d79e26a275c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Addiction</topic><topic>Animals</topic><topic>Antagonist</topic><topic>Binding, Competitive - drug effects</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>DA D3 receptor</topic><topic>Dopamine</topic><topic>Dose-Response Relationship, Drug</topic><topic>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Neuroscience</topic><topic>Pyrroles - chemical synthesis</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Receptors, Dopamine D3 - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Triazoles - chemical synthesis</topic><topic>Triazoles - chemistry</topic><topic>Triazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Micheli, Fabrizio</creatorcontrib><creatorcontrib>Bernardelli, Andrea</creatorcontrib><creatorcontrib>Bianchi, Federica</creatorcontrib><creatorcontrib>Braggio, Simone</creatorcontrib><creatorcontrib>Castelletti, Laura</creatorcontrib><creatorcontrib>Cavallini, Palmina</creatorcontrib><creatorcontrib>Cavanni, Paolo</creatorcontrib><creatorcontrib>Cremonesi, Susanna</creatorcontrib><creatorcontrib>Cin, Michele Dal</creatorcontrib><creatorcontrib>Feriani, Aldo</creatorcontrib><creatorcontrib>Oliosi, Beatrice</creatorcontrib><creatorcontrib>Semeraro, Teresa</creatorcontrib><creatorcontrib>Tarsi, Luca</creatorcontrib><creatorcontrib>Tomelleri, Silvia</creatorcontrib><creatorcontrib>Wong, Andrea</creatorcontrib><creatorcontrib>Visentini, Filippo</creatorcontrib><creatorcontrib>Zonzini, Laura</creatorcontrib><creatorcontrib>Heidbreder, Christian</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><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Micheli, Fabrizio</au><au>Bernardelli, Andrea</au><au>Bianchi, Federica</au><au>Braggio, Simone</au><au>Castelletti, Laura</au><au>Cavallini, Palmina</au><au>Cavanni, Paolo</au><au>Cremonesi, Susanna</au><au>Cin, Michele Dal</au><au>Feriani, Aldo</au><au>Oliosi, Beatrice</au><au>Semeraro, Teresa</au><au>Tarsi, Luca</au><au>Tomelleri, Silvia</au><au>Wong, Andrea</au><au>Visentini, Filippo</au><au>Zonzini, Laura</au><au>Heidbreder, Christian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2016-04-15</date><risdate>2016</risdate><volume>24</volume><issue>8</issue><spage>1619</spage><epage>1636</epage><pages>1619-1636</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26951894</pmid><doi>10.1016/j.bmc.2016.02.031</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-1871-5288</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2016-04, Vol.24 (8), p.1619-1636 |
| issn | 0968-0896 1464-3391 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1790945054 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Addiction Animals Antagonist Binding, Competitive - drug effects CHO Cells Cricetulus DA D3 receptor Dopamine Dose-Response Relationship, Drug Ether-A-Go-Go Potassium Channels - antagonists & inhibitors HEK293 Cells Humans Models, Molecular Molecular Structure Neuroscience Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Receptors, Dopamine D3 - antagonists & inhibitors Structure-Activity Relationship Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology |
| title | 1,2,4-Triazolyl octahydropyrrolo[2,3-b]pyrroles: A new series of potent and selective dopamine D3 receptor antagonists |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T02%3A18%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=1,2,4-Triazolyl%20octahydropyrrolo%5B2,3-b%5Dpyrroles:%20A%20new%20series%20of%20potent%20and%20selective%20dopamine%20D3%20receptor%20antagonists&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry&rft.au=Micheli,%20Fabrizio&rft.date=2016-04-15&rft.volume=24&rft.issue=8&rft.spage=1619&rft.epage=1636&rft.pages=1619-1636&rft.issn=0968-0896&rft.eissn=1464-3391&rft_id=info:doi/10.1016/j.bmc.2016.02.031&rft_dat=%3Cproquest_cross%3E1776629807%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1776629807&rft_id=info:pmid/26951894&rft_els_id=S0968089616301225&rfr_iscdi=true |