Aglycone exploration of C-arylglucoside inhibitors of renal sodium-dependent glucose transporter SGLT2.
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.
Ellsworth
Bruce A
BA
Research and Development, Bristol Myers Squibb Co., PO Box 5400, Princeton, NJ 08543-5400, USA.
Meng
Wei
W
Patel
Manorama
M
Girotra
Ravindar N
RN
Wu
Gang
G
Sher
Philip M
PM
Hagan
Deborah L
DL
Obermeier
Mary T
MT
Humphreys
William G
WG
Robertson
James G
JG
Wang
Aiying
A
Han
Songping
S
Waldron
Thomas L
TL
Morgan
Nathan N
NN
Whaley
Jean M
JM
Washburn
William N
WN
D000818:Animals; D005947:Glucose / Q000737:chemistry; D005960:Glucosides / Q000737:chemistry* / Q000494:pharmacology*; D006030:Glycosuria, Renal / Q000188:drug therapy; D006801:Humans; D007668:Kidney / Q000187:drug effects; D051381:Rats; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D005960:Glucosides; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D005947:Glucose