Aglycone exploration of C-arylglucoside inhibitors of renal sodium-dependent glucose transporter SGLT2

  • Bioorg Med Chem Lett. 2008 Sep 1;18(17):4770-3. doi: 10.1016/j.bmcl.2008.07.109.
Bruce A Ellsworth  1 ,  Wei Meng ,  Manorama Patel ,  Ravindar N Girotra ,  Gang Wu ,  Philip M Sher ,  Deborah L Hagan ,  Mary T Obermeier ,  William G Humphreys ,  James G Robertson ,  Aiying Wang ,  Songping Han ,  Thomas L Waldron ,  Nathan N Morgan ,  Jean M Whaley ,  William N Washburn
Affiliations
  • 1. Research and Development, Bristol Myers Squibb Co., PO Box 5400, Princeton, NJ 08543-5400, USA.
PMID: 18707880 DOI: 10.1016/j.bmcl.2008.07.109
Abstract

Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in Animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4'-substituted benzyl group to a beta-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo.