The low-affinity
sodium glucose cotransporter (SGLT2), which is expressed specifically in the kidney, plays a major role in renal
glucose reabsorption in the proximal tubule. We have discovered
sergliflozin, a prodrug of a novel selective
SGLT2 inhibitor, based on benzylphenol
glucoside. In structure, it belongs to a new category of
SGLT2 inhibitors and its skeleton differs from that of
phlorizin, a nonselective SGLT inhibitor. We investigated its pharmacological properties and potencies in vitro and in vivo. By examining a Chinese hamster ovary-K1 cell line stably expressing either human SGLT2 or human high-affinity
sodium glucose cotransporter (SGLT1), we found
sergliflozin-A (active form) to be a highly selective and potent inhibitor of human SGLT2. At pharmacological doses,
sergliflozin,
sergliflozin-A, and its aglycon had no effects on facilitative
glucose transporter 1 activity, which was inhibited by
phloretin (the aglycon of
phlorizin). The transport maximum for
glucose in the kidney was reduced by
sergliflozin-A in normal rats. As a result of this effect, orally administered
sergliflozin increased urinary
glucose excretion in mice, rats, and dogs in a dose-dependent manner. In an oral
glucose tolerance test in diabetic rats,
sergliflozin exhibited
glucose-lowering effects independently of insulin secretion. Any
glucose excretion induced by
sergliflozin did not affect normoglycemia or electrolyte balance. These data indicate that selective inhibition of SGLT2 increases urinary
glucose excretion by inhibiting renal
glucose reabsorption. As a representative of a new category of
antidiabetic drugs,
sergliflozin may provide a new and unique approach to the treatment of
diabetes mellitus.