Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents

Abstract

Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

Keywords: SGLT2 inhibitor; natural product; phlorizin; sodium-glucose cotransporter; type 2 diabetes mellitus.

Figure 1

Phlorizin and its major O- and C-glucoside analogs.

Figure 2

Chemical structures of active compounds from Sophora flavescens [60,61].

Figure 3

Chemical structures of active compounds from Acer nikoense [62].

Figure 4

Chemical structures of active compounds from Alstonia macrophylla [63].

Figure 5

Chemical structures of active compounds from Gnetum gnemonoides [64].