In Vitro Properties and In Vivo Effect on Urinary Glucose Excretion of BI 10773, a Novel Selective SGLT2 Inhibitor
Abstract Number: 521-P
Authors: ROLF GREMPLER, LEO THOMAS, MATTHIAS ECKHARDT, FRANK HIMMELSBACH, ACHIM SAUER, MICHAEL MARK, PETER EICKELMANN
Institutions: Biberach, Germany
Results: BI 10773 is a novel potent and selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2) which increases urinary glucose excretion. The compound is currently under clinical development for the treatment of type 2 diabetes.
Here, we show the in vitro potency and selectivity of BI 10773 in comparison with another SGLT2 inhibitor in clinical development, remogliflozin etabonate.
For this, human SGLT1, 2, 4 and 5 proteins were stably expressed in Hek293 cells and the uptake of [14C] alpha methyl D-glucopyranoside ([14C]-AMG) was measured. BI 10773 has a higher potency for inhibiting SGLT2 (IC50 3.1±0.7 nM) in comparison to remogliflozin (IC50 12+4 nM). The selectivity of BI 10773 for SGLT2 over SGLT1 is >2500-fold whereas remogliflozin is less selective (> 650-fold). Both compounds are selective for SGLT2 over SGLT4 (IC50 > 10 000 nM) but show a different selectivity towards SGLT5 (BI 10773: 250-fold; remogliflozin: 40-fold).
In addition to the in vitro properties of BI 10773 and remogliflozin, we have investigated the potency of both compounds to induce urinary glucose excretion (UGE) in db/db-mice and ZDF-rats. A single oral dose of 1 mg/kg of each compound led to a similar increase of UGE within the first three hours post application in both animal models. However, the UGE achieved with BI 10773 over 24 hours was significantly higher than that achieved with remogliflozin etabonate in both animal models (example for db/db-mice 24 h UGE: BI 10773: 17.7 mmol glucose/ kg body weight vs. remogliflozin: 9.2 mmol glucose/ kg body weight). In conclusion, our data show that BI 10773 has a better potency for inhibition of SGLT2 than remogliflozin and better selectivity for SGLT2 over SGLT1 and SGLT5. Furthermore, although both compounds increase UGE over 3 h with the same efficacy, BI 10773 is significantly more efficacious over 24 h. This likely reflects a superior pharmacokinetic profile with respect to t1/2 and superior potency of BI 10773 in comparison to remogliflozin etabonate. Our data support the clinical development of BI 10773 for the treatment of type 2 diabetes.