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Molecular Endocrinology

Year: 2009  |  Volume: 23  |  Issue: 7  |  Page No.: 975 - 988

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

F. M Gregoire, F Zhang, H. J Clarke, T. A Gustafson, D. D Sears, S Favelyukis, J Lenhard, D Rentzeperis, L. E Clemens, Y Mu and B. E. Lavan

Abstract

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)- 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- agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR- target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR- agonists, MBX-102 displays differential interactions with the PPAR- 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- or / agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR- modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR- side effects and may represent the next generation insulin sensitizer.

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