PPARG Activator - A new and safer generation of PPARG-specific agonists for the treatment of metabolic diseases

BACKGROUND

Type 2 diabetes is one of the most significant global health concerns: around 400 million people are affected and 5.1 million people died of type 2 diabetes and its complication in 2013.

-> Urgent need to find new types of drugs.

Thiazolidinediones (TZDs) are insulin sensitizers that act through activation of peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are ruined by the risk for sodium and fluid retention, weight gain/lipid storage, bone loss and fractures and congestive heart failure. Most of them were withdrawn from the market.

HOW IT WORKS

New class of organic small molecules, partial PPAR-ɣ agonists (different than TZDs that are full agonist of PPAR-ɣ). Their singular interaction with the PPAR ligand binding domain provide them with unique properties.

KEY BENEFITS

In vitro results:

• Increase insulin sensitivity
• Significant transformation / conversion of the white adipose tissue into brown fat
• Increase in glucose uptake by adipocytes
• Reduction of the inflammatory response of adipocytes
• Reduce adipogenic effect

DEVELOPMENT STATUS

40 analogues synthesized, 1 lead

In vitro model: luminescence (PPARg GAL4 reporter assay)

• Efficacy (EC50): 5 µM versus 0.3 µM for rosiglitazone (TZD)
• Toxicity (CC50): 125 µM on CHO
• Selectivity index (CC50/EC50): 25

APPLICATIONS

Type 2 Diabetes
Nonalcoholic fatty liver disease (NAFLD) / nonalcoholic steatohepatitis (NASH) and hepatic fibrosis
Other potential applications: Cancer, Alzheimer’s disease, Asthma…