Type 2 Diabetes Treatment Pipeline Looks Promising

The creation of novel investigational drugs that target a protein receptor found in fat tissue could pave the way for better treatments for type 2 diabetes.

For the first time, a pair of studies published in the Journal of Medicinal Chemistry and BBA-General Subjects were able to demonstrate how new potential anti-diabetic drugs interact with their target on a molecular level.

The function of these potential drugs differs from the commonly prescribed Metformin, which acts on the liver to reduce glucose production. Instead, they target the protein receptor PPARgamma to either fully or partially activate it to lower blood sugar by increasing insulin sensitivity and altering fat and sugar metabolism.

“Type 2 diabetes is characterized by resistance to insulin with subsequent high blood sugar, which leads to serious disease,” said lead investigator Dr John Bruning. “It is usually associated with poor lifestyle factors such as diet and lack of exercise.

“People with severe diabetes need to take insulin but having to inject this can be problematic, and it’s difficult to get insulin levels just right. It’s highly desirable for people to come off insulin injections and instead use oral therapeutics.”

The need to develop safer and more efficacious drugs to treat type 2 diabetes is increasing in importance as the prevalence of the disease continues to rise.

“[The] prevalence of type 2 diabetes in Australia alone as more than tripled since 1990, with an estimated cost of $6 billion a year,” Dr Bruning said.

The first study was a collaboration with The Scripps Research Institute in Florida, and described an honors research project led by Rebecca Frkic. In the project, 14 different versions of a drug that partially activated PPARgamma were produced with a goal of achieving partial activation that causes fewer adverse events (AEs) compared with full activation.

Currently, the original drug INT131 is being tested in clinical trials in the United States. However, some of the versions produced at the University of Adelaide have increased potency compared with the original, with the potential to further improve type 2 diabetes treatments.

“A major finding of this study was being able to show which regions of the drug are most important for interacting with the PPARgamma receptor,” Dr Bruning said. “This means we now have the information to design modified drugs which will work even more efficiently.”

For the second study, the investigators used X-ray crystallography to demonstrate for the first time precisely how the novel drug rivoglitazone binds with the PPARgamma receptor.

Rivoglitazone does fully activate the PPARgamma, but has considerably less AEs compared with those that have this same mode of action.

“Showing how this compound interacts with its target is a key step towards being able to design new therapeutics with higher efficiencies and less [AEs],” said lead author Dr Rajapaksha. “Lack of structural information was hampering determination of the precise mechanisms involved.”

Reference

• Frkic RL, Rodriquez BB, Chang MR, et al. Structure-Activity Relationship of 2,4-dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPARγ-Targeted Antidiabetics. J Medi Chem. 2017; doi: 10.1021/acs.jmedchem.6b01727