title: Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level.
abstract: 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.
authors.affiliation: Discovery Research Laboratory II, R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Katsuno
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Fujimori
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Takemura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiratochi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Itoh
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujikura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Isaji
mesh_terms: D000042:Absorption; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D004285:Dogs; D004573:Electrolytes / Q000652:urine; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology*; D006029:Glycosuria / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2 / Q000502:physiology; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001786:Blood Glucose; D004573:Electrolytes; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C516973:sergliflozin; D005947:Glucose