Effects of AVE2268, a Substituted Glycopyranoside, on Urinary Glucose Excretion and Blood Glucose in Mice and Rats

verfasst von

Martin Bickel, Harm Brummerhop, Wendelin Frick, Heiner Glombik, Andreas Waldemar Herling, Hubert Otto Heuer, Oliver Plettenburg, Stefan Theis, Ulrich Werner, Werner Kramer

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.

Externe Organisation(en)

Sanofi-Aventis Deutschland GmbH

Typ

Artikel

Journal

Arzneimittel-Forschung/Drug Research

Band

58

Seiten

574-580

Anzahl der Seiten

7

ISSN

0004-4172

Publikationsdatum

11.2008

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Wirkstoffforschung

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1055/s-0031-1296559 (Zugang: Geschlossen)