Title : Novel small molecules for PPARs modulation and their potential use for treatment of metabolic disorders
Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that play a pivotal role in the regulation of glucose homeostasis and lipid metabolism and so they are considered as suitable targets for the treatment of metabolic disorders. These receptors have also been shown to be implicated in cellular proliferation, differentiation, tumor promotion, apoptosis and immune reaction/inflammation. Most recently, it has been highlighted that they also may be involved in the pathogenesis of various disorders of the central nervous system including multiple sclerosis, Alzheimer's and Parkinson's disease.
The search for synthetic ligands towards the different PPAR subtypes (α, γ, δ) has been therefore very extensive and led to the identification of a large number of powerful and selective ligands some of which are currently in therapy as hypolipidemic (PPARα agonists) and antidiabetic (PPARγ agonists) agents. However, subsequent studies have highlighted the important side effects linked to the use of selective and powerful PPAR full agonists, effects that can nullify their therapeutic utility. Therefore, current lines of research focus on the modulation of these receptors as well as the simultaneous activation of different subtypes that seem to be more beneficial for the dissociation of therapeutic activity from adverse side effects.
In this context, for many years our research group has been interested in the synthesis and biological activity of new compounds showing multiple activity towards PPAR receptors. In particular, we identified the lead compound LT175, a dual PPARα/γ ligand with a partial agonism profile toward the γ subtype, that showed an improved therapeutic profile and reduced side effects compared with standard PPARα and PPARγ ligands.
Here we report a novel series of LT175 analogs among which we identified a new ligand whose biological activity was assessed by transactivation assay, gene expression analysis and glucose uptake, inhibition of Cdk5-mediated phosphorylation of PPARγ, and coactivator recruitment assays.
Interestingly, X-ray studies of the complex with PPARγ showed the possibility for this ligand to bind an alternative site besides the canonical one. Although the pharmacological utility of the PPARγ alternative site remains unclear, it is possible that ligands binding this site might favor a correct balance of coactivator and corepressor binding or synergize with endogenous canonical ligands to provide a unique functional activity profile.
Thus, the development of a new generation of PPARγ drugs as alternative modulators targeting non-canonical sites of the ligand binding domain could be a promising approach to address safety concerns and therapeutic profile.
Audience take away:
• synthetic methods and characterization of chiral compounds
• use of small molecules to treat metabolic diseases
• novel applications for PPAR ligands in therapy