Design and Synthesis of Dual Peroxisome Proliferator-Activated Receptors γ and δ Agonists as Novel Euglycemic Agents with a Reduced Weight Gain Profile
The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) γ/δ agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual...
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| Veröffentlicht in: | Journal of medicinal chemistry 2006-09, Vol.49 (19), p.5649-5652 |
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| container_end_page | 5652 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 49 |
| creator | Xu, Yanping Etgen, Garret J Broderick, Carol L Canada, Emily Gonzalez, Isabel Lamar, Jason Montrose-Rafizadeh, Chahrzad Oldham, Brian A Osborne, John J Xie, Chaoyu Shi, Qing Winneroski, Leonard L York, Jeremy Yumibe, Nathan Zink, Richard Mantlo, Nathan |
| description | The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) γ/δ agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR γ/δ agonist profile (IC50 = 19 nM/4 nM; EC50 = 102 nM/6 nM for hPPARγ and hPPARδ, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone. |
| doi_str_mv | 10.1021/jm060617c |
| format | Article |
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The compound possesses a potent dual hPPAR γ/δ agonist profile (IC50 = 19 nM/4 nM; EC50 = 102 nM/6 nM for hPPARγ and hPPARδ, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm060617c</identifier><identifier>PMID: 16970391</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Blood Glucose - metabolism ; Cell Line ; Diabetes Mellitus, Type 2 - drug therapy ; Drug Design ; Dyslipidemias - drug therapy ; Female ; General and cellular metabolism. Vitamins ; Humans ; Hypoglycemic Agents - chemical synthesis ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - pharmacology ; Male ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Phenyl Ethers - chemical synthesis ; Phenyl Ethers - chemistry ; Phenyl Ethers - pharmacology ; Phenylpropionates - chemical synthesis ; Phenylpropionates - chemistry ; Phenylpropionates - pharmacology ; PPAR alpha - genetics ; PPAR delta - agonists ; PPAR gamma - agonists ; Radioligand Assay ; Stereoisomerism ; Transcriptional Activation ; Weight Gain - drug effects</subject><ispartof>Journal of medicinal chemistry, 2006-09, Vol.49 (19), p.5649-5652</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-d30776a73ae60524af9d8245f4870b1f430eb074d54f497a9cca62b22445fafa3</citedby><cites>FETCH-LOGICAL-a381t-d30776a73ae60524af9d8245f4870b1f430eb074d54f497a9cca62b22445fafa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm060617c$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm060617c$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18119279$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16970391$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Yanping</creatorcontrib><creatorcontrib>Etgen, Garret J</creatorcontrib><creatorcontrib>Broderick, Carol L</creatorcontrib><creatorcontrib>Canada, Emily</creatorcontrib><creatorcontrib>Gonzalez, Isabel</creatorcontrib><creatorcontrib>Lamar, Jason</creatorcontrib><creatorcontrib>Montrose-Rafizadeh, Chahrzad</creatorcontrib><creatorcontrib>Oldham, Brian A</creatorcontrib><creatorcontrib>Osborne, John J</creatorcontrib><creatorcontrib>Xie, Chaoyu</creatorcontrib><creatorcontrib>Shi, Qing</creatorcontrib><creatorcontrib>Winneroski, Leonard L</creatorcontrib><creatorcontrib>York, Jeremy</creatorcontrib><creatorcontrib>Yumibe, Nathan</creatorcontrib><creatorcontrib>Zink, Richard</creatorcontrib><creatorcontrib>Mantlo, Nathan</creatorcontrib><title>Design and Synthesis of Dual Peroxisome Proliferator-Activated Receptors γ and δ Agonists as Novel Euglycemic Agents with a Reduced Weight Gain Profile</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) γ/δ agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR γ/δ agonist profile (IC50 = 19 nM/4 nM; EC50 = 102 nM/6 nM for hPPARγ and hPPARδ, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - metabolism</subject><subject>Cell Line</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Drug Design</subject><subject>Dyslipidemias - drug therapy</subject><subject>Female</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Humans</subject><subject>Hypoglycemic Agents - chemical synthesis</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenyl Ethers - chemical synthesis</subject><subject>Phenyl Ethers - chemistry</subject><subject>Phenyl Ethers - pharmacology</subject><subject>Phenylpropionates - chemical synthesis</subject><subject>Phenylpropionates - chemistry</subject><subject>Phenylpropionates - pharmacology</subject><subject>PPAR alpha - genetics</subject><subject>PPAR delta - agonists</subject><subject>PPAR gamma - agonists</subject><subject>Radioligand Assay</subject><subject>Stereoisomerism</subject><subject>Transcriptional Activation</subject><subject>Weight Gain - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU1uEzEYhi0EoqGw4ALIG5BYDPhv7JllaEtBqkpEg2BnffHYicPMONgzpTkK54Bz9Ey4JGo2rCz7ffzYej-EnlPyhhJG3647IomkyjxAE1oyUoiKiIdoQghjBZOMH6EnKa0JIZwy_hgdUVkrwms6Qb9ObfLLHkPf4KttP6zyNuHg8OkILZ7ZGG58Cp3Fsxha72yEIcRiagZ_DYNt8Gdr7CYfJXz7-5_k9g-eLkPv05AwJHwZrm2Lz8ZluzW28yaHts_RTz-sMOTrzWiy5qv1y9WAz8H3dy8539qn6JGDNtln-_UYfXl_Nj_5UFx8Ov94Mr0ogFd0KBpOlJKgOFhJSibA1U3FROlEpciCOsGJXRAlmlI4USuojQHJFoyJzIADfoxe7bybGH6MNg2688nYtoXehjFpWVVCloRn8PUONDGkFK3Tm-g7iFtNib6bg76fQ2Zf7KXjorPNgdwXn4GXewCSgdZF6I1PB66itGaqzlyx43Kh9uY-h_hdS8VVqeezK335bjaX5bdKVwcvmKTXYYx97u4_H_wLTlqtig</recordid><startdate>20060921</startdate><enddate>20060921</enddate><creator>Xu, Yanping</creator><creator>Etgen, Garret J</creator><creator>Broderick, Carol L</creator><creator>Canada, Emily</creator><creator>Gonzalez, Isabel</creator><creator>Lamar, Jason</creator><creator>Montrose-Rafizadeh, Chahrzad</creator><creator>Oldham, Brian A</creator><creator>Osborne, John J</creator><creator>Xie, Chaoyu</creator><creator>Shi, Qing</creator><creator>Winneroski, Leonard L</creator><creator>York, Jeremy</creator><creator>Yumibe, Nathan</creator><creator>Zink, Richard</creator><creator>Mantlo, Nathan</creator><general>American Chemical Society</general><scope>BSCLL</scope><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>20060921</creationdate><title>Design and Synthesis of Dual Peroxisome Proliferator-Activated Receptors γ and δ Agonists as Novel Euglycemic Agents with a Reduced Weight Gain Profile</title><author>Xu, Yanping ; Etgen, Garret J ; Broderick, Carol L ; Canada, Emily ; Gonzalez, Isabel ; Lamar, Jason ; Montrose-Rafizadeh, Chahrzad ; Oldham, Brian A ; Osborne, John J ; Xie, Chaoyu ; Shi, Qing ; Winneroski, Leonard L ; York, Jeremy ; Yumibe, Nathan ; Zink, Richard ; Mantlo, Nathan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-d30776a73ae60524af9d8245f4870b1f430eb074d54f497a9cca62b22445fafa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Glucose - metabolism</topic><topic>Cell Line</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Drug Design</topic><topic>Dyslipidemias - drug therapy</topic><topic>Female</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Humans</topic><topic>Hypoglycemic Agents - chemical synthesis</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenyl Ethers - chemical synthesis</topic><topic>Phenyl Ethers - chemistry</topic><topic>Phenyl Ethers - pharmacology</topic><topic>Phenylpropionates - chemical synthesis</topic><topic>Phenylpropionates - chemistry</topic><topic>Phenylpropionates - pharmacology</topic><topic>PPAR alpha - genetics</topic><topic>PPAR delta - agonists</topic><topic>PPAR gamma - agonists</topic><topic>Radioligand Assay</topic><topic>Stereoisomerism</topic><topic>Transcriptional Activation</topic><topic>Weight Gain - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Yanping</creatorcontrib><creatorcontrib>Etgen, Garret J</creatorcontrib><creatorcontrib>Broderick, Carol L</creatorcontrib><creatorcontrib>Canada, Emily</creatorcontrib><creatorcontrib>Gonzalez, Isabel</creatorcontrib><creatorcontrib>Lamar, Jason</creatorcontrib><creatorcontrib>Montrose-Rafizadeh, Chahrzad</creatorcontrib><creatorcontrib>Oldham, Brian A</creatorcontrib><creatorcontrib>Osborne, John J</creatorcontrib><creatorcontrib>Xie, Chaoyu</creatorcontrib><creatorcontrib>Shi, Qing</creatorcontrib><creatorcontrib>Winneroski, Leonard L</creatorcontrib><creatorcontrib>York, Jeremy</creatorcontrib><creatorcontrib>Yumibe, Nathan</creatorcontrib><creatorcontrib>Zink, Richard</creatorcontrib><creatorcontrib>Mantlo, Nathan</creatorcontrib><collection>Istex</collection><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>Xu, Yanping</au><au>Etgen, Garret J</au><au>Broderick, Carol L</au><au>Canada, Emily</au><au>Gonzalez, Isabel</au><au>Lamar, Jason</au><au>Montrose-Rafizadeh, Chahrzad</au><au>Oldham, Brian A</au><au>Osborne, John J</au><au>Xie, Chaoyu</au><au>Shi, Qing</au><au>Winneroski, Leonard L</au><au>York, Jeremy</au><au>Yumibe, Nathan</au><au>Zink, Richard</au><au>Mantlo, Nathan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and Synthesis of Dual Peroxisome Proliferator-Activated Receptors γ and δ Agonists as Novel Euglycemic Agents with a Reduced Weight Gain Profile</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2006-09-21</date><risdate>2006</risdate><volume>49</volume><issue>19</issue><spage>5649</spage><epage>5652</epage><pages>5649-5652</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) γ/δ agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR γ/δ agonist profile (IC50 = 19 nM/4 nM; EC50 = 102 nM/6 nM for hPPARγ and hPPARδ, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16970391</pmid><doi>10.1021/jm060617c</doi><tpages>4</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Blood Glucose - metabolism Cell Line Diabetes Mellitus, Type 2 - drug therapy Drug Design Dyslipidemias - drug therapy Female General and cellular metabolism. Vitamins Humans Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacology Male Medical sciences Mice Pharmacology. Drug treatments Phenyl Ethers - chemical synthesis Phenyl Ethers - chemistry Phenyl Ethers - pharmacology Phenylpropionates - chemical synthesis Phenylpropionates - chemistry Phenylpropionates - pharmacology PPAR alpha - genetics PPAR delta - agonists PPAR gamma - agonists Radioligand Assay Stereoisomerism Transcriptional Activation Weight Gain - drug effects |
| title | Design and Synthesis of Dual Peroxisome Proliferator-Activated Receptors γ and δ Agonists as Novel Euglycemic Agents with a Reduced Weight Gain Profile |
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