Thiazolidinedione (TZD) are a class of antidiabetes drugs that are agonists for PPARg. However, recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. In this work the authors describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lacking classical transcriptional agonism. These agents block Cdk5-mediated phosphorylation of PPARγ in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the TZDs. In addition, unlike TZDs, SR1664 also did not interfere with bone formation in culture. This work demonstrates the promise of developing novel antidiabetic medications with fewer side effects.
Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, et al Nature.