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Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators
A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD+-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubili...
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| Published in: | Journal of medicinal chemistry 2009-03, Vol.52 (5), p.1275-1283 |
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a344t-314e952a128e973584db65ab658898cf9202a3d1543c0a3968cad90eba1da23b3 |
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| cites | cdi_FETCH-LOGICAL-a344t-314e952a128e973584db65ab658898cf9202a3d1543c0a3968cad90eba1da23b3 |
| container_end_page | 1283 |
| container_issue | 5 |
| container_start_page | 1275 |
| container_title | Journal of medicinal chemistry |
| container_volume | 52 |
| creator | Vu, Chi B Bemis, Jean E Disch, Jeremy S Ng, Pui Yee Nunes, Joseph J Milne, Jill C Carney, David P Lynch, Amy V Smith, Jesse J Lavu, Siva Lambert, Philip D Gagne, David J Jirousek, Michael R Schenk, Simon Olefsky, Jerrold M Perni, Robert B |
| description | A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD+-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model. |
| doi_str_mv | 10.1021/jm8012954 |
| format | article |
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This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm8012954</identifier><identifier>PMID: 19199480</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Type 2 - drug therapy ; Enzyme Activators - chemical synthesis ; Enzyme Activators - chemistry ; Enzyme Activators - pharmacology ; General and cellular metabolism. Vitamins ; Hypoglycemic Agents - chemical synthesis ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - pharmacology ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Quinoxalines - chemical synthesis ; Quinoxalines - chemistry ; Quinoxalines - pharmacology ; Rats ; Rats, Zucker ; Sirtuin 1 - metabolism ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - chemistry ; Thiazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2009-03, Vol.52 (5), p.1275-1283</ispartof><rights>Copyright © 2009 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a344t-314e952a128e973584db65ab658898cf9202a3d1543c0a3968cad90eba1da23b3</citedby><cites>FETCH-LOGICAL-a344t-314e952a128e973584db65ab658898cf9202a3d1543c0a3968cad90eba1da23b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21262351$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19199480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vu, Chi B</creatorcontrib><creatorcontrib>Bemis, Jean E</creatorcontrib><creatorcontrib>Disch, Jeremy S</creatorcontrib><creatorcontrib>Ng, Pui Yee</creatorcontrib><creatorcontrib>Nunes, Joseph J</creatorcontrib><creatorcontrib>Milne, Jill C</creatorcontrib><creatorcontrib>Carney, David P</creatorcontrib><creatorcontrib>Lynch, Amy V</creatorcontrib><creatorcontrib>Smith, Jesse J</creatorcontrib><creatorcontrib>Lavu, Siva</creatorcontrib><creatorcontrib>Lambert, Philip D</creatorcontrib><creatorcontrib>Gagne, David J</creatorcontrib><creatorcontrib>Jirousek, Michael R</creatorcontrib><creatorcontrib>Schenk, Simon</creatorcontrib><creatorcontrib>Olefsky, Jerrold M</creatorcontrib><creatorcontrib>Perni, Robert B</creatorcontrib><title>Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD+-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Enzyme Activators - chemical synthesis</subject><subject>Enzyme Activators - chemistry</subject><subject>Enzyme Activators - pharmacology</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Hypoglycemic Agents - chemical synthesis</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Quinoxalines - chemical synthesis</subject><subject>Quinoxalines - chemistry</subject><subject>Quinoxalines - pharmacology</subject><subject>Rats</subject><subject>Rats, Zucker</subject><subject>Sirtuin 1 - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNpt0N9LwzAQB_AgipvTB_8B6YuIYDWXpFvyODZ_FIaCzieRck1T7GjXmbSD-debseJefDjCkQ933JeQc6C3QBncLSpJgalIHJA-RIyGQlJxSPqUMhayIeM9cuLcglLKgfFj0gMFSnnUJ_G0cLpeG7sJ6jyIqyLDn_oDbliYfjZfhW9KE0yNLdbYFGvjAnTBs_dl8Ba_ziEY62b7VVt3So5yLJ05694BeX-4n0-ewtnLYzwZz0LkQjQhB2FUxBCYNGrEIymydBihLymV1LlilCHPIBJcU-RqKDVmipoUIUPGUz4gV7u5K1t_t8Y1SeVPMGWJS1O3Lhlxv4IJQb283klta-esyZOVLSq0mwRosg0u-QvO24tuaptWJtvLLikPLjuATmOZW1zqwv05BtucI9g71C5Z1K1d-jD-WfgLfKl-uA</recordid><startdate>20090312</startdate><enddate>20090312</enddate><creator>Vu, Chi B</creator><creator>Bemis, Jean E</creator><creator>Disch, Jeremy S</creator><creator>Ng, Pui Yee</creator><creator>Nunes, Joseph J</creator><creator>Milne, Jill C</creator><creator>Carney, David P</creator><creator>Lynch, Amy V</creator><creator>Smith, Jesse J</creator><creator>Lavu, Siva</creator><creator>Lambert, Philip D</creator><creator>Gagne, David J</creator><creator>Jirousek, Michael R</creator><creator>Schenk, Simon</creator><creator>Olefsky, Jerrold M</creator><creator>Perni, Robert B</creator><general>American Chemical Society</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></search><sort><creationdate>20090312</creationdate><title>Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators</title><author>Vu, Chi B ; Bemis, Jean E ; Disch, Jeremy S ; Ng, Pui Yee ; Nunes, Joseph J ; Milne, Jill C ; Carney, David P ; Lynch, Amy V ; Smith, Jesse J ; Lavu, Siva ; Lambert, Philip D ; Gagne, David J ; Jirousek, Michael R ; Schenk, Simon ; Olefsky, Jerrold M ; Perni, Robert B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a344t-314e952a128e973584db65ab658898cf9202a3d1543c0a3968cad90eba1da23b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Diabetes Mellitus, Experimental - drug therapy</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Enzyme Activators - chemical synthesis</topic><topic>Enzyme Activators - chemistry</topic><topic>Enzyme Activators - pharmacology</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Hypoglycemic Agents - chemical synthesis</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Quinoxalines - chemical synthesis</topic><topic>Quinoxalines - chemistry</topic><topic>Quinoxalines - pharmacology</topic><topic>Rats</topic><topic>Rats, Zucker</topic><topic>Sirtuin 1 - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vu, Chi B</creatorcontrib><creatorcontrib>Bemis, Jean E</creatorcontrib><creatorcontrib>Disch, Jeremy S</creatorcontrib><creatorcontrib>Ng, Pui Yee</creatorcontrib><creatorcontrib>Nunes, Joseph J</creatorcontrib><creatorcontrib>Milne, Jill C</creatorcontrib><creatorcontrib>Carney, David P</creatorcontrib><creatorcontrib>Lynch, Amy V</creatorcontrib><creatorcontrib>Smith, Jesse J</creatorcontrib><creatorcontrib>Lavu, Siva</creatorcontrib><creatorcontrib>Lambert, Philip D</creatorcontrib><creatorcontrib>Gagne, David J</creatorcontrib><creatorcontrib>Jirousek, Michael R</creatorcontrib><creatorcontrib>Schenk, Simon</creatorcontrib><creatorcontrib>Olefsky, Jerrold M</creatorcontrib><creatorcontrib>Perni, Robert B</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vu, Chi B</au><au>Bemis, Jean E</au><au>Disch, Jeremy S</au><au>Ng, Pui Yee</au><au>Nunes, Joseph J</au><au>Milne, Jill C</au><au>Carney, David P</au><au>Lynch, Amy V</au><au>Smith, Jesse J</au><au>Lavu, Siva</au><au>Lambert, Philip D</au><au>Gagne, David J</au><au>Jirousek, Michael R</au><au>Schenk, Simon</au><au>Olefsky, Jerrold M</au><au>Perni, Robert B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-03-12</date><risdate>2009</risdate><volume>52</volume><issue>5</issue><spage>1275</spage><epage>1283</epage><pages>1275-1283</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD+-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. 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| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2009-03, Vol.52 (5), p.1275-1283 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Biological and medical sciences Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Type 2 - drug therapy Enzyme Activators - chemical synthesis Enzyme Activators - chemistry Enzyme Activators - pharmacology General and cellular metabolism. Vitamins Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacology Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Medical sciences Mice Pharmacology. Drug treatments Quinoxalines - chemical synthesis Quinoxalines - chemistry Quinoxalines - pharmacology Rats Rats, Zucker Sirtuin 1 - metabolism Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacology |
| title | Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators |
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