SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors
A potent and bioavailable SCD inhibitor, 3j was identified from optimization of a lead thiazole compound and its in vivo SCD inhibition studies are described. Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Co...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (5), p.1593-1597 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Ramtohul, Yeeman K. Black, Cameron Chan, Chi-Chung Crane, Sheldon Guay, Jocelyne Guiral, Sébastien Huang, Zheng Oballa, Renata Xu, Li-Jing Zhang, Lei Li, Chun Sing |
| description | A potent and bioavailable SCD inhibitor,
3j was identified from optimization of a lead thiazole compound and its in vivo SCD inhibition studies are described.
Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound
3j, a potent SCD inhibitor (human HepG2 IC
50
=
1
nM) was identified from the optimization of a lead thiazole compound
MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2
mg/kg,
3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels. |
| doi_str_mv | 10.1016/j.bmcl.2010.01.083 |
| format | Article |
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3j was identified from optimization of a lead thiazole compound and its in vivo SCD inhibition studies are described.
Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound
3j, a potent SCD inhibitor (human HepG2 IC
50
=
1
nM) was identified from the optimization of a lead thiazole compound
MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2
mg/kg,
3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.01.083</identifier><identifier>PMID: 20137926</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Administration, Oral ; Animals ; Biological and medical sciences ; Body weight gain prevention ; Desaturation index ; Dietary Fats ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - toxicity ; General and cellular metabolism. Vitamins ; Hep G2 Cells ; Humans ; Hypoglycemic Agents - chemical synthesis ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - toxicity ; Insulin and glucose sensitivity ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Oxadiazoles - chemical synthesis ; Oxadiazoles - chemistry ; Oxadiazoles - toxicity ; Pharmacology. Drug treatments ; SCD inhibitors ; Stearoyl-CoA Desaturase - antagonists & inhibitors ; Stearoyl-CoA Desaturase - metabolism ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - chemistry ; Thiazoles - toxicity ; Weight Gain</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-03, Vol.20 (5), p.1593-1597</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-ea0f55459175e4d3572a28a4f2728ac3ca0865e7925a0b5b8416eb14237210fe3</citedby><cites>FETCH-LOGICAL-c417t-ea0f55459175e4d3572a28a4f2728ac3ca0865e7925a0b5b8416eb14237210fe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X10000958$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22824750$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20137926$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ramtohul, Yeeman K.</creatorcontrib><creatorcontrib>Black, Cameron</creatorcontrib><creatorcontrib>Chan, Chi-Chung</creatorcontrib><creatorcontrib>Crane, Sheldon</creatorcontrib><creatorcontrib>Guay, Jocelyne</creatorcontrib><creatorcontrib>Guiral, Sébastien</creatorcontrib><creatorcontrib>Huang, Zheng</creatorcontrib><creatorcontrib>Oballa, Renata</creatorcontrib><creatorcontrib>Xu, Li-Jing</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Li, Chun Sing</creatorcontrib><title>SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A potent and bioavailable SCD inhibitor,
3j was identified from optimization of a lead thiazole compound and its in vivo SCD inhibition studies are described.
Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound
3j, a potent SCD inhibitor (human HepG2 IC
50
=
1
nM) was identified from the optimization of a lead thiazole compound
MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2
mg/kg,
3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Body weight gain prevention</subject><subject>Desaturation index</subject><subject>Dietary Fats</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - toxicity</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Hypoglycemic Agents - chemical synthesis</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - toxicity</subject><subject>Insulin and glucose sensitivity</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Oxadiazoles - chemical synthesis</subject><subject>Oxadiazoles - chemistry</subject><subject>Oxadiazoles - toxicity</subject><subject>Pharmacology. Drug treatments</subject><subject>SCD inhibitors</subject><subject>Stearoyl-CoA Desaturase - antagonists & inhibitors</subject><subject>Stearoyl-CoA Desaturase - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - toxicity</subject><subject>Weight Gain</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1rFEEQhhsxmDX6BzzIXMTTbKq_pmfBy7LEDwgIasBbU9NTY3qZmV67e4Xk19vrruZmTgVVT71VPIy94rDkwJvL7bKb3LgUUBrAl9DKJ2zBVaNqqUA_ZQtYNVC3K_X9nD1PaQvAFSj1jJ2XFWlWolmwm6_rLxXOfRV22U_-HrMPcxWGKt96vA8jlSGO4UeqMFW7kGnOVcqEMdyN9Sasq54S5n3ERJWfb33nc4jpBTsbcEz08lQv2M37q2-bj_X15w-fNuvr2iluck0Ig9ZKr7jRpHqpjUDRohqEKcVJh9A2msqnGqHTXat4Qx1XQhrBYSB5wd4ec3cx_NxTynbyydE44kxhn6xRupFat_JxUspyS5imkOJIuhhSijTYXfQTxjvLwR682609eLcH7xa4hT_xr0_x-26i_t_KX9EFeHMCMDkch4iz8-mBE61QRkPh3h05Ktp-eYo2OU-zo95Hctn2wf_vj9_5tZ_u</recordid><startdate>20100301</startdate><enddate>20100301</enddate><creator>Ramtohul, Yeeman K.</creator><creator>Black, Cameron</creator><creator>Chan, Chi-Chung</creator><creator>Crane, Sheldon</creator><creator>Guay, Jocelyne</creator><creator>Guiral, Sébastien</creator><creator>Huang, Zheng</creator><creator>Oballa, Renata</creator><creator>Xu, Li-Jing</creator><creator>Zhang, Lei</creator><creator>Li, Chun Sing</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>IQODW</scope><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></search><sort><creationdate>20100301</creationdate><title>SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors</title><author>Ramtohul, Yeeman K. ; Black, Cameron ; Chan, Chi-Chung ; Crane, Sheldon ; Guay, Jocelyne ; Guiral, Sébastien ; Huang, Zheng ; Oballa, Renata ; Xu, Li-Jing ; Zhang, Lei ; Li, Chun Sing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-ea0f55459175e4d3572a28a4f2728ac3ca0865e7925a0b5b8416eb14237210fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Body weight gain prevention</topic><topic>Desaturation index</topic><topic>Dietary Fats</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - toxicity</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Hypoglycemic Agents - chemical synthesis</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Hypoglycemic Agents - toxicity</topic><topic>Insulin and glucose sensitivity</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Oxadiazoles - chemical synthesis</topic><topic>Oxadiazoles - chemistry</topic><topic>Oxadiazoles - toxicity</topic><topic>Pharmacology. Drug treatments</topic><topic>SCD inhibitors</topic><topic>Stearoyl-CoA Desaturase - antagonists & inhibitors</topic><topic>Stearoyl-CoA Desaturase - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - toxicity</topic><topic>Weight Gain</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ramtohul, Yeeman K.</creatorcontrib><creatorcontrib>Black, Cameron</creatorcontrib><creatorcontrib>Chan, Chi-Chung</creatorcontrib><creatorcontrib>Crane, Sheldon</creatorcontrib><creatorcontrib>Guay, Jocelyne</creatorcontrib><creatorcontrib>Guiral, Sébastien</creatorcontrib><creatorcontrib>Huang, Zheng</creatorcontrib><creatorcontrib>Oballa, Renata</creatorcontrib><creatorcontrib>Xu, Li-Jing</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Li, Chun Sing</creatorcontrib><collection>Pascal-Francis</collection><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 letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ramtohul, Yeeman K.</au><au>Black, Cameron</au><au>Chan, Chi-Chung</au><au>Crane, Sheldon</au><au>Guay, Jocelyne</au><au>Guiral, Sébastien</au><au>Huang, Zheng</au><au>Oballa, Renata</au><au>Xu, Li-Jing</au><au>Zhang, Lei</au><au>Li, Chun Sing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-03-01</date><risdate>2010</risdate><volume>20</volume><issue>5</issue><spage>1593</spage><epage>1597</epage><pages>1593-1597</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A potent and bioavailable SCD inhibitor,
3j was identified from optimization of a lead thiazole compound and its in vivo SCD inhibition studies are described.
Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound
3j, a potent SCD inhibitor (human HepG2 IC
50
=
1
nM) was identified from the optimization of a lead thiazole compound
MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2
mg/kg,
3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20137926</pmid><doi>10.1016/j.bmcl.2010.01.083</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-03, Vol.20 (5), p.1593-1597 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_745635583 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Oral Animals Biological and medical sciences Body weight gain prevention Desaturation index Dietary Fats Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - toxicity General and cellular metabolism. Vitamins Hep G2 Cells Humans Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Hypoglycemic Agents - toxicity Insulin and glucose sensitivity Medical sciences Mice Mice, Inbred C57BL Oxadiazoles - chemical synthesis Oxadiazoles - chemistry Oxadiazoles - toxicity Pharmacology. Drug treatments SCD inhibitors Stearoyl-CoA Desaturase - antagonists & inhibitors Stearoyl-CoA Desaturase - metabolism Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - toxicity Weight Gain |
| title | SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors |
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