PT  - JOURNAL ARTICLE
AU  - Masayuki Suzuki
AU  - Kiyofumi Honda
AU  - Masanori Fukazawa
AU  - Kazuharu Ozawa
AU  - Hitoshi Hagita
AU  - Takahiro Kawai
AU  - Minako Takeda
AU  - Tatsuo Yata
AU  - Mio Kawai
AU  - Taku Fukuzawa
AU  - Takamitsu Kobayashi
AU  - Tsutomu Sato
AU  - Yoshiki Kawabe
AU  - Sachiya Ikeda
TI  - Tofogliflozin, a Potent and Highly Specific Sodium/Glucose Cotransporter 2 Inhibitor, Improves Glycemic Control in Diabetic Rats and Mice
AID  - 10.1124/jpet.112.191593
DP  - 2012 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 692--701
VI  - 341
IP  - 3
4099  - http://jpet.aspetjournals.org/content/341/3/692.short
4100  - http://jpet.aspetjournals.org/content/341/3/692.full
SO  - J Pharmacol Exp Ther2012 Jun 01; 341
AB  - 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 Ki 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.