Towards a safe treatment of Insulin Resistance: γ-hydroxy lactone-based derivatives as PPARγ non-agonists

Insulin resistance is a pathological condition characterized by attenuated tissue response to normal or elevated insulin production. Type 2 diabetes mellitus (T2DM) and Metabolic Syndrome are the most common clinical pathologies associated with IR. Type 2 diabetes mellitus (T2DM) is a major health issue that has reached alarming levels. Today, more than half a billion people are living with diabetes worldwide [1]. Moreover, most of glitazones, the traditional anti-diabetic drugs, which act as Peroxisome proliferator-activated receptor γ (PPARγ) agonist, have been withdrawn from the market. To avoid the serious adverse effects related to the PPARγ agonism profile, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser245 [2]. Recently, we disclosed the PPARγ non-agonist activity of 4-(4-bromophenyl)-3 hydroxy-5-(3-hydroxyphenyl)furan-2(5H)-one (1), which is able to block the phosphorylation of the enzyme without direct inhibition effect of both CDK5 and PPARγ [2]. Crystallographic experiments allowed us to deeply investigate the interaction of 1 with PPARγ, and the co-crystal data (PDB: 8ADF) [2] were used as starting point for the computational studies, leading to optimized derivatives of 1, endowed with higher affinity for PPARγ. Of note, an innovative green synthetic approach was tackled in several steps, where the traditional organic solvents were replaced with bio-based solvents derived from biowaste, or from very cheap and easily accessible natural sources. The results of this study will be presented, evidencing that the γ-hydroxy-lactone scaffold may provide a promising template for the development of a novel and safe treatment of Insulin Resistance.