Novel alpha-Glucosidase and alpha-Galactosidase Inhibitors as Antidiabetic, Antiviral Drugs and as Pharmacological Chaperones for Pompe Disease
The global α-glucosidase inhibitors market generated $ 4069 million in 2018 and is expected to grow at a CAGR of 2% during 2019-2024. Acarbose, Miglitol, and Voglibose are the most prescribed alpha-glucosidase inhibitors used in the management of hyperglycemia for the treatment of type 2 diabetes mellitus. On the other hand, the combination of small α-glucosidase inhibitors as pharmacological chaperones (PCs) with enzyme replacement therapy (ERT) has shown a synergic effect in improved enzyme activity and reduction of toxic metabolites. Therefore, it is expected that the co-treatment PC-ERT may reduce the amount of ERT necessary to achieve the desired pharmacological effect and therefore may lower lysosomal storage diseases (LSDs) treatment cost. Current ERT is very costly, ranging between € 9 - € 10 million (£ 7.9 - £ 8.8 million, $ 13.0- $ 14. 5 million) during a patient's lifetime. No PC-ERT treatment for Pompe disease exists. Last but not least, recent studies have demonstrated that
ER α-glucosidases I and II are essential for the morphorgenesis of many enveloped viruses, and various iminosugar-based ER α-glucosidase inhibitors has shown in vivo antiviral efficacy in animals infected with Dengue, Ebola and influenza viruses.
Leiden University have developed a new class of α-glucosidase inhibitors names α-cyclosulfamidates.
α-Glucosidase configured cyclosumaidates react reversibly or irreversibly with diverse human α-glucosidases depedning on the nitrogen position of the cyclic sulfamidate. They have shown that the reversible α-cyclosulfamidate is able to stabilize the recombinant lysosomal human α-glucosidase (GAA) in in vitro and in situ cell experiments and increased enzyme activity is observed in the medium of the cells co-treated with this α- cyclosulfamidate and recombinant GAA. Herein they describe the potential treatment of Diabetes and / or viral infections, as well as the potential of the reversible analogue as stabilizer of GAA for the treatment for Pompe patients in combination with ERT.
This invention provides a set of new α-glucosidase and α-galactosidase inhibitors. α-Glucosidase inhibitors have shown beneficial effects in multiple applications (antidiabetics, antiviral and as pharmacological chaperones for Pompe disease). Various combinations of enzyme replacement therapy or (mult) gene therapies with a pharmacological chaperone (glycosidase inhibitor) for the treatment of lysosomal storage diseases and glycosidase deficiency related diseases, particularly Fabry, Gaucher or Pompe disease. This combination optimizes the clinical benefit, ie, reduced enzyme treatment, while minimizing disadvantages associated with ERT.
- α-Glucosidase inhibitors are known to delay the absorption of carbohydrates and find application as oral antidiabetic.
- Recently, ER- α-glucosidase I and II inhibitors have also demonstrated potential antiviral therapeutic.
- In relation to lysosomal storage disorders, the combination of PC and ERT may reduce the amount of ERT necessary to achieve the desired pharmacologic effect.
- When administered in combination with enzyme to cells, the compound stabilizes the recombinant enzyme and prevent its degradation.
A structure activity relationship (SAR) on the glucose configured cyclosulfamidate is ongoing and their effect in an in vivo model is under study.
Patent application submitted