Dual targeting of PTP1B and glucosidases with new bifunctional iminosugar inhibitors to address type 2 diabetes

• Published in: Bioorganic chemistry 2019-06, Vol.87, p.534-549
• Main Authors: Ferhati, Xhenti, Matassini, Camilla, Fabbrini, Maria Giulia, Goti, Andrea, Morrone, Amelia, Cardona, Francesca, Moreno-Vargas, Antonio J., Paoli, Paolo
• Format: Article
• Language: English
• Subjects: Bifunctional compounds; Iminosugars; Insulin-mimetic activity; PTP1B inhibitors; Type 2 diabetes; α-glucosidase inhibitors
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.03.053

[Display omitted] •Developing new anti-diabetic drugs is an urgent challenge for worldwide population.•Multi-target drugs offer new therapeutic opportunities.•Nitrobenzene iminosugar hybrids can target both PTP1B and α-glucosidase enzymes.•Bifunctional iminosugars show insulin-mimetic activity in HepG2 cells. The diffusion of type 2 diabetes (T2D) throughout the world represents one of the most important health problems of this century. Patients suffering from this disease can currently be treated with numerous oral anti-hyperglycaemic drugs, but none is capable of reproducing the physiological action of insulin and, in several cases, they induce severe side effects. Developing new anti-diabetic drugs remains one of the most urgent challenges of the pharmaceutical industry. Multi-target drugs could offer new therapeutic opportunities for the treatment of T2D, and the reported data on type 2 diabetic mice models indicate that these drugs could be more effective and have fewer side effects than mono-target drugs. α-Glucosidases and Protein Tyrosine Phosphatase 1B (PTP1B) are considered important targets for the treatment of T2D: the first digest oligo- and disaccharides in the gut, while the latter regulates the insulin-signaling pathway. With the aim of generating new drugs able to target both enzymes, we synthesized a series of bifunctional compounds bearing both a nitro aromatic group and an iminosugar moiety. The results of tests carried out both in vitro and in a cell-based model, show that these bifunctional compounds maintain activity on both target enzymes and, more importantly, show a good insulin-mimetic activity, increasing phosphorylation levels of Akt in the absence of insulin stimulation. These compounds could be used to develop a new generation of anti-hyperglycemic drugs useful for the treatment of patients affected by T2D.