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 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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- T2D
- type 2 diabetes mellitus
- 2DG
- 2-deoxy-glucose
- AMG
- methyl-α-d-glucopyranoside
- ATCC
- American Type Culture Collection
- CMC
- carboxymethyl cellulose
- Glu AUC
- blood glucose area under the curve
- GSIS
- glucose-stimulated insulin secretion
- IRI
- immunoreactive insulin
- MI
- myo-inositol
- SGLT
- sodium/glucose cotransporter
- SMIT
- sodium/myo-inositol transporter
- UGE
- urinary glucose excretion
- CHO
- Chinese hamster ovary
- ZDF
- Zucker diabetic fatty
- h
- human
- r
- rat
- m
- mouse
- OGTT
- oral glucose tolerance test
- PF-04971729
- (1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-(hydroxymethyl)-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol.
- Received January 10, 2012.
- Accepted March 9, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|