| MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema. | |
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MedLine Citation:
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PMID: 19389808 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-gamma that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-gamma agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-gamma target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-gamma agonists, MBX-102 displays differential interactions with the PPAR-gamma ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-gamma or alpha/gamma agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-gamma modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-gamma side effects and may represent the next generation insulin sensitizer. |
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Authors:
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Francine M Gregoire; Fang Zhang; Holly J Clarke; Thomas A Gustafson; Dorothy D Sears; Svetlana Favelyukis; James Lenhard; Dennis Rentzeperis; L Edward Clemens; Yi Mu; Brian E Lavan |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-04-23 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 23 ISSN: 1944-9917 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-06-29 Completed Date: 2009-10-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 975-88 Citation Subset: IM |
Affiliation:
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Metabolex, Department of Biology, Hayward, California 94545, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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3T3-L1 Cells Adipocytes / drug effects, metabolism Animals Cells, Cultured Diabetes Mellitus, Type 2 / drug therapy Drug Evaluation, Preclinical Drug Partial Agonism Edema / chemically induced, prevention & control* Halofenate / adverse effects, pharmacology*, therapeutic use Humans Hypoglycemic Agents / adverse effects*, pharmacology*, therapeutic use Insulin Resistance / physiology Male Mice Mice, Inbred C57BL Models, Biological PPAR gamma / agonists* Rats Rats, Zucker Stereoisomerism Substrate Specificity / drug effects Thiazolidinediones / adverse effects, pharmacology, therapeutic use Transcriptional Activation / drug effects* Weight Gain / drug effects* |
| Chemical | |
Reg. No./Substance:
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0/Hypoglycemic Agents; 0/PPAR gamma; 0/Thiazolidinediones; 26718-25-2/Halofenate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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