Dual targeting of PTP1B and glucosidases with new bifunctional iminosugar inhibitors to address type 2 diabetes
| Autor: | Amelia Morrone, Paolo De Paoli, Francesca Cardona, Xhenti Ferhati, Andrea Goti, Camilla Matassini, Maria Giulia Fabbrini, Antonio J. Moreno-Vargas |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.drug_class
medicine.medical_treatment Molecular Conformation Iminosugar Type 2 diabetes Pharmacology 01 natural sciences Biochemistry Structure-Activity Relationship Drug Discovery medicine Humans Hypoglycemic Agents Molecular Biology Protein kinase B Protein Tyrosine Phosphatase Non-Receptor Type 1 chemistry.chemical_classification Alpha-glucosidase inhibitor type 2 diabetes bifunctional compounds alpha--glucosidase inhibitors PTP1B inhibitors iminosugars insulin-mimetic activity Dose-Response Relationship Drug biology 010405 organic chemistry Insulin Organic Chemistry Hep G2 Cells medicine.disease Imino Sugars 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Diabetes Mellitus Type 2 chemistry biology.protein Phosphorylation Glucosidases |
| Zdroj: | Bioorganic Chemistry. 87:534-549 |
| ISSN: | 0045-2068 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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