Synthesis of Benzyl C‐Analogues of Dapagliflozin as Potential SGLT2 Inhibitors

Abstract

Sodium‐glucose co‐transporter (SGLT) inhibitors are a novel class of therapeutic agents for the treatment of type 2 diabetes based on blocking of renal reabsorption of glucose. Dapagliflozin, a C‐aryl glucoside, has emerged as a successful drug in the market based on this concept. We have synthesized hitherto unreported C‐benzyl glucoside analogues of Dapagliflozin carrying the same aglycon present in the drug. The synthetic strategy involves in situ generation of functionalized arylmagnesium bromide with Weinreb‐amide (WA) functionality for the first time, and addition on to the 1‐β‐formyl‐2,3,4,6‐tetra‐O‐benzyl‐D‐glucopyranoside for the synthesis of a C‐benzyl glucoside building block 16. The WA functionality therein enabled variation in the nature of the distal ring of biarylmethane aglycon for convenient access to other analogues. All the new compounds were screened for their sodium‐glucose co‐transporters (SGLT1 and SGLT2) inhibition activity using cell‐based nonradioactive fluorescence glucose uptake assay. Among them, 14 with IC50: 0.64 nm emerged as the most potent SGLT2 inhibitor with the best selectivity for inhibition of SGLT2 (IC50:0.64 nm) over SGLT1 (IC50: 500 nm) as compare to Dapagliflozin. On the other hand, compound 15a exhibited moderate selectivity for inhibition of SGLT2 (IC50: 4.94 nm) over SGLT1 (IC50: 68.46 nm). These results presented herein amply demonstrate the promise of C‐benzyl analogues of Dapagliflozin as novel SGLT2 inhibitors for future investigations.