title: Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models.
abstract: The low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes. We have discovered remogliflozin etabonate, which is a novel category of selective SGLT2 inhibitors. Remogliflozin etabonate is a prodrug based on benzylpyrazole glucoside and is metabolized to its active form, remogliflozin, in the body. We identified remogliflozin to be a potent and highly selective SGLT2 inhibitor by examining COS-7 cells transiently expressing either high-affinity sodium glucose cotransporter (SGLT1) or SGLT2. Orally administered remogliflozin etabonate increased urinary glucose excretion in a dose-dependent manner in both mice and rats. By increasing urinary glucose excretion, remogliflozin etabonate inhibited the increase in plasma glucose after glucose loading without stimulating insulin secretion in normal rats. Remogliflozin etabonate also showed antihyperglycemic effects in both streptozotocin-induced diabetic rats in oral glucose tolerance and in db/db mice in the fed condition. Chronic treatment with remogliflozin etabonate reduced the levels of fasting plasma glucose and glycated hemoglobin, and it ameliorated glucosuria in db/db mice. In high-fat diet-fed Goto-Kakizaki rats, remogliflozin etabonate improved hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and insulin resistance. This study demonstrates that treatment with remogliflozin etabonate exhibits antidiabetic efficacy in several rodent models and suggests that remogliflozin etabonate may be a new and useful drug for the treatment of diabetes.
authors.affiliation: Development Research R&D, Kissei Pharmaceutical Co., Ltd., 4365-1, Hotaka, Azumino, Nagano 399-8304, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Fujimori
authors.forename: Kenji
authors.initials: K
authors.lastname: Katsuno
authors.forename: Ikumi
authors.initials: I
authors.lastname: Nakashima
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ishikawa-Takemura
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujikura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Isaji
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology*; D006029:Glycosuria / Q000139:chemically induced; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D005960:Glucosides; D007004:Hypoglycemic Agents; D011720:Pyrazoles; C089180:SLC5A2 protein, human; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C532127:remogliflozin etabonate