Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents.
BACKGROUND
A critical factor for maintenance of glucose balance is the renal recovery of glucose from the glomerular filtrate mediated primarily by sodium glucose co-transporter 2 (SGLT2). This capacity can be modulated by SGLT2 inhibitors thereby providing a unique insulin independent method of treatment of diabetes.


OBJECTIVE
A discussion of the evolution of SGLT inhibitors as inferred from patents published from 2005 to 2009 is prefaced by a brief review of the role of SGLT in glucose transport and the clinical findings illustrating the therapeutic potential of SGLT inhibitors as anti-diabetic agents. These compounds comprise O, C and N-glycosides generated by attachment of an appropriate lipophilic aglycone component to a suitable glucose analogue.


CONCLUSIONS
The realization that the in vivo potency of O-glucosides was markedly less than that of C-glucosides necessitated a shift in medicinal chemistry focus of the pharmaceutical companies pursuing SGLT2 inhibitors. Particular emphasis is placed on the strategy that each used to circumvent the constraints imposed by prior art while utilizing a common pharmacophore. The role of SGLT2 inhibitors for treatment of diabetes will be established by the outcome of the five compounds in advanced clinical trials.
Washburn
William N
WN
Senior Research Fellow, Metabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, USA. william.washburn@bms.com
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D015195:Drug Design; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010330:Patents as Topic; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors