title: 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.
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)-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.
authors.affiliation: Metabolex, Department of Biology, Hayward, California 94545, USA.
authors.forename: Francine M
authors.initials: FM
authors.lastname: Gregoire
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Clarke
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gustafson
authors.forename: Dorothy D
authors.initials: DD
authors.lastname: Sears
authors.forename: Svetlana
authors.initials: S
authors.lastname: Favelyukis
authors.forename: James
authors.initials: J
authors.lastname: Lenhard
authors.forename: Dennis
authors.initials: D
authors.lastname: Rentzeperis
authors.forename: L Edward
authors.initials: LE
authors.lastname: Clemens
authors.forename: Yi
authors.initials: Y
authors.lastname: Mu
authors.forename: Brian E
authors.initials: BE
authors.lastname: Lavan
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D054333:Drug Partial Agonism; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D006218:Halofenate / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D011924:Rats, Zucker; D013237:Stereoisomerism; D013379:Substrate Specificity / Q000187:drug effects; D045162:Thiazolidinediones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D015533:Transcriptional Activation / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D006218:Halofenate