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
| Autor: | Fang Zhang, Dennis Rentzeperis, Francine M. Gregoire, Holly J. Clarke, Brian Edward Lavan, Thomas A. Gustafson, Svetlana Favelyukis, Dorothy D. Sears, L. Edward Clemens, James M. Lenhard, Yi Mu |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Transcriptional Activation Agonist medicine.medical_specialty medicine.drug_class Drug Evaluation Preclinical Peroxisome proliferator-activated receptor Biology Weight Gain Models Biological Partial agonist Substrate Specificity Mice Transactivation Endocrinology 3T3-L1 Cells Internal medicine Adipocytes medicine Animals Edema Humans Hypoglycemic Agents Receptor Molecular Biology Cells Cultured Original Research Transrepression chemistry.chemical_classification Stereoisomerism General Medicine Ligand (biochemistry) Rats Rats Zucker Cell biology Drug Partial Agonism Mice Inbred C57BL PPAR gamma Diabetes Mellitus Type 2 chemistry Thiazolidinediones Peroxisome proliferator-activated receptor alpha Insulin Resistance Halofenate |
| Zdroj: | Molecular Endocrinology. 23:975-988 |
| ISSN: | 1944-9917 0888-8809 3965-9100 |
| DOI: | 10.1210/me.2008-0473 |
| Popis: | 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)-γ 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-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ 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-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer. |
| Databáze: | OpenAIRE |
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