The new study confirms that blockage of Cdk5's action on PPARG is a viable therapeutic approach for development of anti-diabetic agents. The new SR1664 compound is a potent binder to the nuclear receptor PPARG, but does not activate gene transcription via the receptor's normal mechanism.
While Griffin stressed the difficulty of fully assessing side effects of new compounds such as SR1664, the new research is extremely positive in that it clearly demonstrated fewer of the major well-documented side effects, such as weight gain or increased plasma volume, from SR1664 as compared to Avandia in diabetic mice.
While both the mice treated with Avandia and those treated with SR1664 demonstrated improved blood sugar levels, those treated with Avandia showed weight gain and increased fluid retention within a few days of beginning treatment; those being treated with SR1664 showed none of these side effects. In cell culture studies, SR1664 also appeared to have little effect on bone formation, nor did it increase fat generation in bone cells, another side effect of current therapies such as Avandia.
While S1664 likely will not be developed as a drug, it now serves as a molecular scaffolding for the creation of similar compounds with potential to treat diabetes. "With data in hand showing that our compounds are as efficacious as the currently marketed PPARG modulators, while demonstrating a significant improvement of side effects in limited studies, we are now advancing newer compounds with improved pharmaceutical properties into additional studies," Griffin said.
The first authors, denoted as equal contributors to this study, "Anti-Diabetic Actions of a Non-Agonist PPARG Liga
|Contact: Mika Ono|
Scripps Research Institute