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

Mol Endocrinol. 2009 Jul;23(7):975-88. doi: 10.1210/me.2008-0473. Epub 2009 Apr 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / drug therapy
  • Drug Evaluation, Preclinical
  • Drug Partial Agonism
  • Edema / chemically induced
  • Edema / prevention & control*
  • Halofenate / adverse effects
  • Halofenate / pharmacology*
  • Halofenate / therapeutic use
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / 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
  • Thiazolidinediones / pharmacology
  • Thiazolidinediones / therapeutic use
  • Transcriptional Activation / drug effects*
  • Weight Gain / drug effects*


  • Hypoglycemic Agents
  • PPAR gamma
  • Thiazolidinediones
  • Halofenate