List of the scientific projects that received grants

Coordinators:

• INSERM U545 : Bart Staels
• INSERM U761 : Julie Charton

Mission:

Discovery and optimization of TGR5 ligands as pharmacological tools and potential therapeutic agents for the treatment of diseases linked to cholesterol and bile acid metabolism and homeostasis. Feeding the drug discovery pipeline in the therapeutic area of metabolic syndrome and its complications.

Objectives and Rationale:

The metabolic syndrome (MS) can be defined as a cluster of biological and clinical abnormalities including combined dyslipidemia (elevated concentrations of triglycerides-rich and small low-density lipoprotein (LDL) particles and low levels of high-density lipoprotein cholesterol (HDL-C)), insulin resistance or type 2 diabetes (T2D), overweight or obesity, and elevated blood pressure. Each of these abnormalities constitutes an independent risk factor of atherosclerosis, so patients with MS are at high risk of developing cardio-vascular disease (CVD) and to progress to diabetes . MS affects at least 10 % of the French adult population and epidemiological studies project an increase over the future years associated with morbi-mortality affecting several millions of people. MS constitutes therefore a public health problem associated with high financial cost. Patients with the MS require clinical management to reduce the risk of developing CVD. The first treatment strategy for affected persons involves the modification of lifestyle factors (weight loss and increased physical activity). Unfortunately, because of the long-term inefficacy of this approach, combined drug treatment for the individual metabolic risk factors often ensues. The drugs should aim at normalization of insulin resistance/hyperglycemia, lipid abnormalities and overweight. However, at the present time, the drugs available to treat features of the MS are unsatisfactory. The efficacy of the treatments is often insufficient in the long-term, and some of them display deleterious secondary effects. It appears necessary to progress toward an innovative medication in a major area of public health. The receptors TGR5 appear as emerging targets for the treatment of the metabolic syndrome and its complications. Therefore, the objectives of the present project are to:

1. design / discover compounds that induce, in a relevant animal model, a phenotype indicative of the desired clinical effects on MS: - glucose homeostasis and insulin sensitivity improvement, - dyslipidemia correction, - overweight or obesity reduction,
2. propose compounds for progression to an early development candidate.