title: Effects of AVE2268, a substituted glycopyranoside, on urinary glucose excretion and blood glucose in mice and rats.
abstract: AVE2268, a substituted glycopyranoside, is an orally active and selective inhibitor of sodium-dependent glucose transporter 2 (SGLT2; IC50 = 13 nmol/L). Investigation of the pharmacological profile of AVE2268 on urinary glucose excretion (UGE) and blood glucose after glucose challenge (po or Intraperitoneal) was performed in mice and rats. AVE2268 caused a dose-dependent increase of UGE in mice (ID30 = 79 +/- 8.1 mg/kg p.o.) and rats (ID30 = 39.8 +/- 4.0 mg/kg p.o.). AVE2268 in mice was more potent to decrease blood glucose ascent when glucose was given intraperitoneally (ID50 = 13.2 +/- 3.9 mg/ kg), compared to orally administered glucose (ID50 = 26.1 +/- 3.9 mg/kg), showing that AVE2268 has no effects on SGLT 1 in the gut in vivo, which is in accordance with ist very low affinity to the SGLT 1 in vitro (IC50 >10,000 nmol/L). During an oral glucose tolerance test, AVE2268 dose-dependently increased UGE, with subsequent decreases of AUC and blood glucose. A highly significant inverse correlation between AUC and UGE was found (p < 0.001). The increase in UGE is linked to the inhibition of SGLT2 only. This profile renders AVE2268 as a new antidiabetic drug for the treatment of type 2 diabetes.
authors.affiliation: Research & Development, TD Metabolism, Sanofi-Aventis, Frankfurt/Main, Germany. martin.bickel@gmx.de
authors.forename: Martin
authors.initials: M
authors.lastname: Bickel
authors.forename: Harm
authors.initials: H
authors.lastname: Brummerhop
authors.forename: Wendelin
authors.initials: W
authors.lastname: Frick
authors.forename: Heiner
authors.initials: H
authors.lastname: Glombik
authors.forename: Andreas Waldemar
authors.initials: AW
authors.lastname: Herling
authors.forename: Hubert Otto
authors.initials: HO
authors.lastname: Heuer
authors.forename: Oliver
authors.initials: O
authors.lastname: Plettenburg
authors.forename: Stefan
authors.initials: S
authors.lastname: Theis
authors.forename: Ulrich
authors.initials: U
authors.lastname: Werner
authors.forename: Werner
authors.initials: W
authors.lastname: Kramer
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D005960:Glucosides / Q000494:pharmacology*; D006029:Glycosuria / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010695:Phlorhizin / Q000494:pharmacology; D051381:Rats; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: C535206:AVE2268; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D010695:Phlorhizin; D005947:Glucose