Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects
We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-01, Vol.24 (2), p.526-531 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 531 |
|---|---|
| container_issue | 2 |
| container_start_page | 526 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 24 |
| creator | Sun, Shaoyi Zhang, Zaihui Raina, Vandna Pokrovskaia, Natalia Hou, Duanjie Namdari, Rostam Khakh, Kuldip Ratkay, Leslie G. McLaren, David G. Mork, Monica Fu, Jianmin Ferreira, Suzie Hubbard, Brian Winther, Michael D. Dales, Natalie |
| description | We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles. |
| doi_str_mv | 10.1016/j.bmcl.2013.12.035 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1500781866</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X13014078</els_id><sourcerecordid>1500781866</sourcerecordid><originalsourceid>FETCH-LOGICAL-c389t-1f37ce8a6bb51353010b71a62f4f4aaefa2832974b4e7849a57f92b70987590d3</originalsourceid><addsrcrecordid>eNp9kEtr3DAUhUVpaKZp_0AXRctu7Oply4ZuyqQvCHSRFLoTknzF3MG2ppKdMN3ln1fDpF12dbnwnQPnI-QNZzVnvH2_r93kx1owLmsuaiabZ2TDVasqqVjznGxY37Kq69XPS_Iy5z1jXDGlXpBLoaQun9iQx2vMPt5DOtIY6LJD-zuOx_FwTDjgHGegt9trTnHeocMlpkwfcNnRQ4IACeYF7UhHLHk6YF4SunXBOFM7DzTBsHoY6AR-Z2fMU-VsLr8dCp6BQgjgl_yKXAQ7Znj9dK_Ij8-f7rZfq5vvX75tP95UXnb9UvEgtYfOts41XDaSceY0t60IKihrIVjRSdFr5RToTvW20aEXTrO-003PBnlF3p17Dyn-WiEvZirTYRztDHHNhjeM6Y53bVtQcUZ9ijmXqeaQcLLpaDgzJ_Vmb07qzUm94cIU9SX09ql_dRMM_yJ_XRfgwxmAsvIeIZnsEeaiCFMRYYaI_-v_A2wul4s</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1500781866</pqid></control><display><type>article</type><title>Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Sun, Shaoyi ; Zhang, Zaihui ; Raina, Vandna ; Pokrovskaia, Natalia ; Hou, Duanjie ; Namdari, Rostam ; Khakh, Kuldip ; Ratkay, Leslie G. ; McLaren, David G. ; Mork, Monica ; Fu, Jianmin ; Ferreira, Suzie ; Hubbard, Brian ; Winther, Michael D. ; Dales, Natalie</creator><creatorcontrib>Sun, Shaoyi ; Zhang, Zaihui ; Raina, Vandna ; Pokrovskaia, Natalia ; Hou, Duanjie ; Namdari, Rostam ; Khakh, Kuldip ; Ratkay, Leslie G. ; McLaren, David G. ; Mork, Monica ; Fu, Jianmin ; Ferreira, Suzie ; Hubbard, Brian ; Winther, Michael D. ; Dales, Natalie</creatorcontrib><description>We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2013.12.035</identifier><identifier>PMID: 24370012</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Caco-2 Cells ; Desaturation index ; Dose-Response Relationship, Drug ; Drug Discovery - methods ; Eyelid ; Hep G2 Cells ; Humans ; Liver - drug effects ; Liver - metabolism ; Liver selective ; Mice ; Pyridones - chemistry ; Pyridones - metabolism ; Pyridones - pharmacology ; Rats ; Rats, Inbred Lew ; SCD1 inhibitors ; Stearoyl-CoA Desaturase - antagonists & inhibitors ; Stearoyl-CoA Desaturase - metabolism ; Stearoyl-CoA desaturase-1 ; Thiazolylpyridinone ; Tissue Distribution - drug effects ; Tissue Distribution - physiology</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-01, Vol.24 (2), p.526-531</ispartof><rights>2013 Elsevier Ltd</rights><rights>Copyright © 2013 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-1f37ce8a6bb51353010b71a62f4f4aaefa2832974b4e7849a57f92b70987590d3</citedby><cites>FETCH-LOGICAL-c389t-1f37ce8a6bb51353010b71a62f4f4aaefa2832974b4e7849a57f92b70987590d3</cites><orcidid>0000-0002-2946-9510</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X13014078$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24370012$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Shaoyi</creatorcontrib><creatorcontrib>Zhang, Zaihui</creatorcontrib><creatorcontrib>Raina, Vandna</creatorcontrib><creatorcontrib>Pokrovskaia, Natalia</creatorcontrib><creatorcontrib>Hou, Duanjie</creatorcontrib><creatorcontrib>Namdari, Rostam</creatorcontrib><creatorcontrib>Khakh, Kuldip</creatorcontrib><creatorcontrib>Ratkay, Leslie G.</creatorcontrib><creatorcontrib>McLaren, David G.</creatorcontrib><creatorcontrib>Mork, Monica</creatorcontrib><creatorcontrib>Fu, Jianmin</creatorcontrib><creatorcontrib>Ferreira, Suzie</creatorcontrib><creatorcontrib>Hubbard, Brian</creatorcontrib><creatorcontrib>Winther, Michael D.</creatorcontrib><creatorcontrib>Dales, Natalie</creatorcontrib><title>Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.</description><subject>Animals</subject><subject>Caco-2 Cells</subject><subject>Desaturation index</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery - methods</subject><subject>Eyelid</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver selective</subject><subject>Mice</subject><subject>Pyridones - chemistry</subject><subject>Pyridones - metabolism</subject><subject>Pyridones - pharmacology</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>SCD1 inhibitors</subject><subject>Stearoyl-CoA Desaturase - antagonists & inhibitors</subject><subject>Stearoyl-CoA Desaturase - metabolism</subject><subject>Stearoyl-CoA desaturase-1</subject><subject>Thiazolylpyridinone</subject><subject>Tissue Distribution - drug effects</subject><subject>Tissue Distribution - physiology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtr3DAUhUVpaKZp_0AXRctu7Oply4ZuyqQvCHSRFLoTknzF3MG2ppKdMN3ln1fDpF12dbnwnQPnI-QNZzVnvH2_r93kx1owLmsuaiabZ2TDVasqqVjznGxY37Kq69XPS_Iy5z1jXDGlXpBLoaQun9iQx2vMPt5DOtIY6LJD-zuOx_FwTDjgHGegt9trTnHeocMlpkwfcNnRQ4IACeYF7UhHLHk6YF4SunXBOFM7DzTBsHoY6AR-Z2fMU-VsLr8dCp6BQgjgl_yKXAQ7Znj9dK_Ij8-f7rZfq5vvX75tP95UXnb9UvEgtYfOts41XDaSceY0t60IKihrIVjRSdFr5RToTvW20aEXTrO-003PBnlF3p17Dyn-WiEvZirTYRztDHHNhjeM6Y53bVtQcUZ9ijmXqeaQcLLpaDgzJ_Vmb07qzUm94cIU9SX09ql_dRMM_yJ_XRfgwxmAsvIeIZnsEeaiCFMRYYaI_-v_A2wul4s</recordid><startdate>20140115</startdate><enddate>20140115</enddate><creator>Sun, Shaoyi</creator><creator>Zhang, Zaihui</creator><creator>Raina, Vandna</creator><creator>Pokrovskaia, Natalia</creator><creator>Hou, Duanjie</creator><creator>Namdari, Rostam</creator><creator>Khakh, Kuldip</creator><creator>Ratkay, Leslie G.</creator><creator>McLaren, David G.</creator><creator>Mork, Monica</creator><creator>Fu, Jianmin</creator><creator>Ferreira, Suzie</creator><creator>Hubbard, Brian</creator><creator>Winther, Michael D.</creator><creator>Dales, Natalie</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><orcidid>https://orcid.org/0000-0002-2946-9510</orcidid></search><sort><creationdate>20140115</creationdate><title>Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects</title><author>Sun, Shaoyi ; Zhang, Zaihui ; Raina, Vandna ; Pokrovskaia, Natalia ; Hou, Duanjie ; Namdari, Rostam ; Khakh, Kuldip ; Ratkay, Leslie G. ; McLaren, David G. ; Mork, Monica ; Fu, Jianmin ; Ferreira, Suzie ; Hubbard, Brian ; Winther, Michael D. ; Dales, Natalie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-1f37ce8a6bb51353010b71a62f4f4aaefa2832974b4e7849a57f92b70987590d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Caco-2 Cells</topic><topic>Desaturation index</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery - methods</topic><topic>Eyelid</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver selective</topic><topic>Mice</topic><topic>Pyridones - chemistry</topic><topic>Pyridones - metabolism</topic><topic>Pyridones - pharmacology</topic><topic>Rats</topic><topic>Rats, Inbred Lew</topic><topic>SCD1 inhibitors</topic><topic>Stearoyl-CoA Desaturase - antagonists & inhibitors</topic><topic>Stearoyl-CoA Desaturase - metabolism</topic><topic>Stearoyl-CoA desaturase-1</topic><topic>Thiazolylpyridinone</topic><topic>Tissue Distribution - drug effects</topic><topic>Tissue Distribution - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Shaoyi</creatorcontrib><creatorcontrib>Zhang, Zaihui</creatorcontrib><creatorcontrib>Raina, Vandna</creatorcontrib><creatorcontrib>Pokrovskaia, Natalia</creatorcontrib><creatorcontrib>Hou, Duanjie</creatorcontrib><creatorcontrib>Namdari, Rostam</creatorcontrib><creatorcontrib>Khakh, Kuldip</creatorcontrib><creatorcontrib>Ratkay, Leslie G.</creatorcontrib><creatorcontrib>McLaren, David G.</creatorcontrib><creatorcontrib>Mork, Monica</creatorcontrib><creatorcontrib>Fu, Jianmin</creatorcontrib><creatorcontrib>Ferreira, Suzie</creatorcontrib><creatorcontrib>Hubbard, Brian</creatorcontrib><creatorcontrib>Winther, Michael D.</creatorcontrib><creatorcontrib>Dales, Natalie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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 letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Shaoyi</au><au>Zhang, Zaihui</au><au>Raina, Vandna</au><au>Pokrovskaia, Natalia</au><au>Hou, Duanjie</au><au>Namdari, Rostam</au><au>Khakh, Kuldip</au><au>Ratkay, Leslie G.</au><au>McLaren, David G.</au><au>Mork, Monica</au><au>Fu, Jianmin</au><au>Ferreira, Suzie</au><au>Hubbard, Brian</au><au>Winther, Michael D.</au><au>Dales, Natalie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2014-01-15</date><risdate>2014</risdate><volume>24</volume><issue>2</issue><spage>526</spage><epage>531</epage><pages>526-531</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24370012</pmid><doi>10.1016/j.bmcl.2013.12.035</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-2946-9510</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2014-01, Vol.24 (2), p.526-531 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1500781866 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Caco-2 Cells Desaturation index Dose-Response Relationship, Drug Drug Discovery - methods Eyelid Hep G2 Cells Humans Liver - drug effects Liver - metabolism Liver selective Mice Pyridones - chemistry Pyridones - metabolism Pyridones - pharmacology Rats Rats, Inbred Lew SCD1 inhibitors Stearoyl-CoA Desaturase - antagonists & inhibitors Stearoyl-CoA Desaturase - metabolism Stearoyl-CoA desaturase-1 Thiazolylpyridinone Tissue Distribution - drug effects Tissue Distribution - physiology |
| title | Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T05%3A42%3A34IST&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=Discovery%20of%20thiazolylpyridinone%20SCD1%20inhibitors%20with%20preferential%20liver%20distribution%20and%20reduced%20mechanism-based%20adverse%20effects&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Sun,%20Shaoyi&rft.date=2014-01-15&rft.volume=24&rft.issue=2&rft.spage=526&rft.epage=531&rft.pages=526-531&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2013.12.035&rft_dat=%3Cproquest_cross%3E1500781866%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=1500781866&rft_id=info:pmid/24370012&rft_els_id=S0960894X13014078&rfr_iscdi=true |