MK-0767, a novel dual PPARα/γ agonist, displays robust antihyperglycemic and hypolipidemic activities
Here, we characterize the actions of MK-0767, a dual ligand of the nuclear receptors peroxisome proliferator-activated receptor (PPAR)α and PPARγ. In cell-based assays, MK-0767 produced potent activation of human PPARγ and PPARα with a γ:α potency ratio of ≈2. The dual agonist induced high affinity...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2004-05, Vol.318 (2), p.323-328 |
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| container_title | Biochemical and biophysical research communications |
| container_volume | 318 |
| creator | Doebber, Thomas W Kelly, Linda J Zhou, Gaochao Meurer, Roger Biswas, Chhabi Li, Ying Wu, Margaret S Ippolito, Marc C Chao, Yu-Sheng Wang, Pei-Ran Wright, Samuel D Moller, David E Berger, Joel P |
| description | Here, we characterize the actions of MK-0767, a dual ligand of the nuclear receptors peroxisome proliferator-activated receptor (PPAR)α and PPARγ. In cell-based assays, MK-0767 produced potent activation of human PPARγ and PPARα with a γ:α potency ratio of ≈2. The dual agonist induced high affinity interactions of PPARα and PPARγ with the transcriptional coactivator CBP in vitro. In ob/ob mice, MK-0767 normalized hyperglycemia and hyperinsulinemia with equal or greater potency and efficacy than pioglitazone. Treatment of hamsters with MK-0767 produced substantial reductions in blood cholesterol and triglycerides. In dogs, MK-0767 reduced serum cholesterol levels with a potency more than 10-fold greater than simvastatin. The efficacies of MK-0767 and simvastatin were additive when given together. We conclude that MK-0767 is a potent dual PPARα/γ agonist with robust insulin sensitizing and hypolipidemic activities. |
| doi_str_mv | 10.1016/j.bbrc.2004.04.032 |
| format | Article |
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We conclude that MK-0767 is a potent dual PPARα/γ agonist with robust insulin sensitizing and hypolipidemic activities.</description><subject>Dyslipidemia</subject><subject>Hyperglycemia</subject><subject>Insulin sensitizer</subject><subject>Peroxisome proliferator-activated receptor</subject><subject>Type 2 diabetes</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNp9kM1Kw0AUhQdRsFZfwNWsXDXpnZ8mBtyU4h9WLOrC3TCd3NQpaRJnkkIeS3yPPpMJcS0cuJfDORfuR8glg5ABi6bbcL12JuQAMuwl-BEZMUgg4AzkMRkBQBTwhH2ckjPvtwCMySgZkc3zUwBxFE-opkW5x5ymjc7pajV_PXxPDz9Ub8rC-npCU-urXLeeunLd-JrqorafbYVuk7cGd9Z0Tko7p8xtZdPBMbXd29qiPycnmc49XvzNMXm7u31fPATLl_vHxXwZGCFYHeg41jEKk0WgU4mzmTBGZFmaaZ7E3EjBeJQkDE1s1oyhSGTCo1hy3q3XKMbkarhaufKrQV-rnfUG81wXWDZeceBSCJBdkA9B40rvHWaqcnanXasYqJ6o2qqeqOqJql6Cd6WboYTdA3uLTnljsTCYWoemVmlp_6v_AqlRgN0</recordid><startdate>20040528</startdate><enddate>20040528</enddate><creator>Doebber, Thomas W</creator><creator>Kelly, Linda J</creator><creator>Zhou, Gaochao</creator><creator>Meurer, Roger</creator><creator>Biswas, Chhabi</creator><creator>Li, Ying</creator><creator>Wu, Margaret S</creator><creator>Ippolito, Marc C</creator><creator>Chao, Yu-Sheng</creator><creator>Wang, Pei-Ran</creator><creator>Wright, Samuel D</creator><creator>Moller, David E</creator><creator>Berger, Joel P</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20040528</creationdate><title>MK-0767, a novel dual PPARα/γ agonist, displays robust antihyperglycemic and hypolipidemic activities</title><author>Doebber, Thomas W ; Kelly, Linda J ; Zhou, Gaochao ; Meurer, Roger ; Biswas, Chhabi ; Li, Ying ; Wu, Margaret S ; Ippolito, Marc C ; Chao, Yu-Sheng ; Wang, Pei-Ran ; Wright, Samuel D ; Moller, David E ; Berger, Joel P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c331t-a77a7e3cf60ad4e553cc3ffdfa2972c43126991ec7cb11e3949267422e398e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Dyslipidemia</topic><topic>Hyperglycemia</topic><topic>Insulin sensitizer</topic><topic>Peroxisome proliferator-activated receptor</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Doebber, Thomas W</creatorcontrib><creatorcontrib>Kelly, Linda J</creatorcontrib><creatorcontrib>Zhou, Gaochao</creatorcontrib><creatorcontrib>Meurer, Roger</creatorcontrib><creatorcontrib>Biswas, Chhabi</creatorcontrib><creatorcontrib>Li, Ying</creatorcontrib><creatorcontrib>Wu, Margaret S</creatorcontrib><creatorcontrib>Ippolito, Marc C</creatorcontrib><creatorcontrib>Chao, Yu-Sheng</creatorcontrib><creatorcontrib>Wang, Pei-Ran</creatorcontrib><creatorcontrib>Wright, Samuel D</creatorcontrib><creatorcontrib>Moller, David E</creatorcontrib><creatorcontrib>Berger, Joel P</creatorcontrib><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>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Doebber, Thomas W</au><au>Kelly, Linda J</au><au>Zhou, Gaochao</au><au>Meurer, Roger</au><au>Biswas, Chhabi</au><au>Li, Ying</au><au>Wu, Margaret S</au><au>Ippolito, Marc C</au><au>Chao, Yu-Sheng</au><au>Wang, Pei-Ran</au><au>Wright, Samuel D</au><au>Moller, David E</au><au>Berger, Joel P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MK-0767, a novel dual PPARα/γ agonist, displays robust antihyperglycemic and hypolipidemic activities</atitle><jtitle>Biochemical and biophysical research communications</jtitle><date>2004-05-28</date><risdate>2004</risdate><volume>318</volume><issue>2</issue><spage>323</spage><epage>328</epage><pages>323-328</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>Here, we characterize the actions of MK-0767, a dual ligand of the nuclear receptors peroxisome proliferator-activated receptor (PPAR)α and PPARγ. In cell-based assays, MK-0767 produced potent activation of human PPARγ and PPARα with a γ:α potency ratio of ≈2. The dual agonist induced high affinity interactions of PPARα and PPARγ with the transcriptional coactivator CBP in vitro. In ob/ob mice, MK-0767 normalized hyperglycemia and hyperinsulinemia with equal or greater potency and efficacy than pioglitazone. Treatment of hamsters with MK-0767 produced substantial reductions in blood cholesterol and triglycerides. In dogs, MK-0767 reduced serum cholesterol levels with a potency more than 10-fold greater than simvastatin. The efficacies of MK-0767 and simvastatin were additive when given together. We conclude that MK-0767 is a potent dual PPARα/γ agonist with robust insulin sensitizing and hypolipidemic activities.</abstract><pub>Elsevier Inc</pub><doi>10.1016/j.bbrc.2004.04.032</doi><tpages>6</tpages></addata></record> |
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| source | Elsevier ScienceDirect Journals |
| subjects | Dyslipidemia Hyperglycemia Insulin sensitizer Peroxisome proliferator-activated receptor Type 2 diabetes |
| title | MK-0767, a novel dual PPARα/γ agonist, displays robust antihyperglycemic and hypolipidemic activities |
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