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
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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DOI：
10.1210/me.2008-0473
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发表时间：
2009-07-01
影响因子：
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通讯作者：
Lavan, Brian E.
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文献类型：
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作者：
Gregoire, Francine M.;Zhang, Fang;Lavan, Brian E.
MBX-102/JNJ 39659100（MBX-102）正在临床开发中，作为治疗2型糖尿病的口服降糖药。MBX-102是过氧化物酶体增殖物激活受体（PPAR）-γ的非噻唑烷二酮（TZD）选择性部分激动剂，在结构、机制、临床前和临床上与TZD不同。在糖尿病啮齿动物模型中，MBX-102具有与TZD相当的胰岛素增敏和降糖特性，而体重没有剂量依赖性增加。在体外，与完全PPAR-gamma激动剂处理相反，MBX-102不能驱动人和鼠脂肪细胞分化，并且选择性地调节成熟脂肪细胞中PPAR-gamma靶基因子集的表达。此外，MBX-102不抑制鼠间充质细胞的成骨细胞生成。与完全的PPAR-gamma激动剂相比，MBX-102显示出与PPAR-gamma配体结合结构域的差异性相互作用，并且具有降低的募集共激活剂的能力。有趣的是，在原代小鼠巨噬细胞中，MBX-102与其他PPAR-gamma或alpha/gamma激动剂相比显示出增强的抑制特性，表明MBX-102具有更有效的反式阻遏活性。总之，MBX-102是具有弱反式激活但具有强反式阻遏活性的选择性PPAR-gamma调节剂。MBX-102表现出完全的治疗活性，没有典型的PPAR-gamma副作用，可能代表下一代胰岛素增敏剂。（分子内分泌学23：975-988，2009）
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. (Molecular Endocrinology 23: 975-988, 2009)