title: Tofogliflozin, a potent and highly specific sodium/glucose cotransporter 2 inhibitor, improves glycemic control in diabetic rats and mice.
abstract: Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Honda
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukazawa
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Ozawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hagita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kawai
authors.forename: Minako
authors.initials: M
authors.lastname: Takeda
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yata
authors.forename: Mio
authors.initials: M
authors.lastname: Kawai
authors.forename: Taku
authors.initials: T
authors.lastname: Fukuzawa
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
authors.forename: Sachiya
authors.initials: S
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D018149:Glucose Intolerance / Q000188:drug therapy; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol