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Fluorine‐Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes
Author(s) -
Sadurní Anna,
Kehr Gerald,
Ahlqvist Marie,
Wernevik Johan,
Sjögren Helena Peilot,
Kankkonen Cecilia,
Knerr Laurent,
Gilmour Ryan
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201705373
Subject(s) - dapagliflozin , phlorizin , glycosylation , renal glucose reabsorption , chemistry , pyranose , clearance , empagliflozin , pharmacology , type 2 diabetes , diabetes mellitus , medicine , biochemistry , glucose transporter , endocrinology , insulin , urology
Inhibition of the sodium‐glucose co‐transporters (SGLT1 and SGLT2) is a validated strategy to address the increasing prevalence of type II diabetes mellitus . However, achieving selective inhibition of human SGLT1 or SGLT2 remains challenging. Orally available small molecule drugs based on the d ‐glucose core of the natural product Gliflozin have proven to be clinically effective in this regard, effectively impeding glucose reabsorption. Herein, we disclose the influence of molecular editing with fluorine at the C2 position of the pyranose ring of Phlorizin analogues Remogliflozin Etabonate and Dapagliflozin (Farxiga ® ) to concurrently direct β‐selective glycosylation, as is required for biological efficacy, and enhance aspects of the physicochemical profile. Given the abundance of glycosylated pharmaceuticals in diabetes therapy that contain a β‐configured d ‐glucose nucleus, it is envisaged that this strategy may prove to be expansive.