Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents

Abstract

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.

Pharmacodynamic Model of Sodium–Glucose Transporter 2 (SGLT2) Inhibition: Implications for Quantitative Translational Pharmacology

“…Within the T2DM therapeutic area, the sodium-glucose co-transporter 2 (SGLT2) target represents one of the most competitive areas of R&D (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Glucose entering the glomerulus through passive filtration is reabsorbed by the combined actions of SGLT2 and SGLT1 in the S1 and S3 segments of the proximal tubule, respectively.…”

“…Other attractive features of this mechanism include its non-insulin-dependent nature and the potential for weight loss due to the caloric loss associated with UGE. As such, it is one of the top eight targets being pursued in the pharmaceutical industry and there are several novel SGLT2 inhibitors currently in clinical development (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). While several compounds have attrited in phase I and II, clinical results with the most advanced SGLT2 inhibitor, dapagliflozin, indicate that clinically significant HbA1c reductions are possible with this target (23,24).…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…SGLT2 inhibition as a therapeutic target was encouraged and accelerated by the knowledge of mutations in the SGLT2 gene, called "kidney diabetes," which results in renal glucosuria with no danger of a hypoglycemia (van den Heuvel et al, 2002;Calado et al, 2004). SGLT2 inhibitors have the advantage of being an insulin-independent treatment option (Washburn, 2009). Every 1 g of glucose excreted into the urine equates to ϳ4 kcal of energy.…”

“…Novel SGLT2 inhibitors having different chemical, pharmacodynamic, and pharmacokinetic profiles have been reviewed (Kees et al, 1996;Link and Sorensen, 2000;Ohsumi et al, 2003;Zhang et al, 2005Zhang et al, , 2006Isaji, 2007;Abdul-Ghani and DeFronzo, 2008;Idris and Donnelly, 2009;Washburn, 2009). These compounds comprise O-, C-and N-glycosides generated by attachment of an appropriate lipophilic aglycone component to a suitable glucose analog (Washburn, 2009)…”

An Emerging Protagonist: Sodium Glucose Co-transporters (SGLTs) as a Burgeoning Target for the Treatment of Diabetes Mellitus

“…Thus a new therapeutic approach without dependence on insulin and appropriate for use in amalgamation with other agents would be preeminent choice for treatment of hyperglycemia in type 2 diabetes mellitus (T2DM). Sodium Glucose co-transporter inhibitors create a center of attention as there is a need of potential therapy for diabetes mellitus with lesser side effects [4,5]. This review scrutinize the niceties of various SGLT2 inhibitors…”