FXR-Agonists

Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. FXR is highly expressed in the liver, intestine, adrenal gland and kidney. Recent studies indicate an important role for nuclear receptors in regulating lipid and carbohydrate metabolism, fibrosis and inflammation. The nuclear receptor FXR modulates gene transcription by interacting with co-regulators upon ligand binding. As shown below, FXR has pleiotropic effects on various cardiometabolic parameters.

FXR Mechanism of Action

FXR agonists induce a strong decrease in cholesterol synthesis and release by the liver. They also deeply decrease circulating triglycerides as well as liver accumulation. The effect on glycemic control is less clear. However, reducing triglycerides concentration in the liver may improve insulin resistance. It may also improve or protect against dysglycemia. By targeting both lipids and glucose metabolism and by irmproving insulin resistance, FXR agonists may be of great interest in cardiovascular disease prevention and treatment.

Ligand-based and structure-based pharmacophore models are currently built in collaboration with a CRO.

Innovative, diverse and drug-like chemical series have been identified, and rapid compound optimizations based on 3D-information have been performed.

Poxel’s project is currently at a lead optimization stage and already demonstrated positive effects in preclinical diabetic animal models.