Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition
The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors{,} and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1{,}3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks’ protocols{,} although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h{,} identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg−1 and ∼43% at 60 mg kg−1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.
Références
- Titre
- Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition
- Type de publication
- Article de revue
- Année de publication
- 2020
- Auteurs
- Goyard, David, Kónya Bálint, Czifrák Katalin, Larini Paolo, Demontrond Fanny, Leroy Jérémy, Balzarin Sophie, Tournier Michel, Tousch Didier, Petit Pierre, Duret Cédric, Maurel Patrick, Docsa Tibor, Gergely Pál, Somsák László, Praly Jean-Pierre, Azay-Milhau Jacqueline, and Vidal Sebastien
- Revue
- Org. Biomol. Chem.
- Volume
- 18
- Pagination
- 931-940
- Date de publication
- 01/2020
Soumis le 14 janvier 2020