Indole-glucosides as novel sodium glucose co-transporter 2 (SGLT2) inhibitors. Part 2

Zhang, Xiaoyan; Urbanski, Maud; Patel, Mona; Cox, Geoffrey G.; Zeck, Roxanne E.; Bian, Haiyan; Conway, Bruce R.; Beavers, Mary Pat; Rybczynski, Philip J.; Demarest, Keith T.

doi:10.1016/j.bmcl.2005.12.006

Cited by 25 publications

(12 citation statements)

References 16 publications

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“…2). Although several human SGLT inhibitors have been reported to date, detailed analysis of their selectivity for human Link and Sorensen, 2000;Ohsumi et al, 2003;Zhang et al, 2005Zhang et al, , 2006. According to Oku et al (1999), the selectivity ratio of T-1095A is approximately 4 .…”

Section: Discussionmentioning

confidence: 99%

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Katsuno

Fujimori²,

Takemura³

et al. 2006

J Pharmacol Exp Ther

247

183

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The low-affinity sodium glucose cotransporter (SGLT2), which is expressed specifically in the kidney, plays a major role in renal glucose reabsorption in the proximal tubule. We have discovered sergliflozin, a prodrug of a novel selective SGLT2 inhibitor, based on benzylphenol glucoside. In structure, it belongs to a new category of SGLT2 inhibitors and its skeleton differs from that of phlorizin, a nonselective SGLT inhibitor. We investigated its pharmacological properties and potencies in vitro and in vivo. By examining a Chinese hamster ovary-K1 cell line stably expressing either human SGLT2 or human highaffinity sodium glucose cotransporter (SGLT1), we found sergliflozin-A (active form) to be a highly selective and potent inhibitor of human SGLT2. At pharmacological doses, sergliflozin, sergliflozin-A, and its aglycon had no effects on facilitative glucose transporter 1 activity, which was inhibited by phloretin (the aglycon of phlorizin). The transport maximum for glucose in the kidney was reduced by sergliflozin-A in normal rats. As a result of this effect, orally administered sergliflozin increased urinary glucose excretion in mice, rats, and dogs in a dosedependent manner. In an oral glucose tolerance test in diabetic rats, sergliflozin exhibited glucose-lowering effects independently of insulin secretion. Any glucose excretion induced by sergliflozin did not affect normoglycemia or electrolyte balance. These data indicate that selective inhibition of SGLT2 increases urinary glucose excretion by inhibiting renal glucose reabsorption. As a representative of a new category of antidiabetic drugs, sergliflozin may provide a new and unique approach to the treatment of diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Katsuno

Fujimori²,

Takemura³

et al. 2006

J Pharmacol Exp Ther

247

183

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“…There is no consensus as to whether SGLT1 inhibition is needed in addition to SGLT2 inhibition. Several researchers reported on other SGLT inhibitors (Kees et al, 1996;Link and Sorensen, 2000;Ohsumi et al, 2003;Zhang et al, 2005Zhang et al, , 2006Isaji, 2007). We have developed a selective SGLT2 inhibitor, sergliflozin, which is a prodrug based on benzylphenol glucoside (Katsuno et al, 2007).…”

mentioning

confidence: 99%

Remogliflozin Etabonate, in a Novel Category of Selective Low-Affinity Sodium Glucose Cotransporter (SGLT2) Inhibitors, Exhibits Antidiabetic Efficacy in Rodent Models

Fujimori

Katsuno²,

Nakashima³

et al. 2008

J Pharmacol Exp Ther

197

167

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The low-affinity sodium glucose cotransporter (SGLT2) plays an important role in renal glucose reabsorption and is a remarkable transporter as a molecular target for the treatment of diabetes. We have discovered remogliflozin etabonate, which is a novel category of selective SGLT2 inhibitors. Remogliflozin etabonate is a prodrug based on benzylpyrazole glucoside and is metabolized to its active form, remogliflozin, in the body. We identified remogliflozin to be a potent and highly selective SGLT2 inhibitor by examining COS-7 cells transiently expressing either high-affinity sodium glucose cotransporter (SGLT1) or SGLT2. Orally administered remogliflozin etabonate increased urinary glucose excretion in a dose-dependent manner in both mice and rats. By increasing urinary glucose excretion, remogliflozin etabonate inhibited the increase in plasma glucose after glucose loading without stimulating insulin secretion in normal rats. Remogliflozin etabonate also showed antihyperglycemic effects in both streptozotocin-induced diabetic rats in oral glucose tolerance and in db/db mice in the fed condition. Chronic treatment with remogliflozin etabonate reduced the levels of fasting plasma glucose and glycated hemoglobin, and it ameliorated glucosuria in db/db mice. In high-fat diet-fed Goto-Kakizaki rats, remogliflozin etabonate improved hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and insulin resistance. This study demonstrates that treatment with remogliflozin etabonate exhibits antidiabetic efficacy in several rodent models and suggests that remogliflozin etabonate may be a new and useful drug for the treatment of diabetes.

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“…It is now well established that suppressing the activity of SGLT2 inhibits renal glucose reabsorption, thereby increasing the excretion of excess glucose from the body and assisting in the reduction of hyper-glycemia in T2DM (Oku et al, 1999;Adachi et al, 2000;Zhang et al, 2005Zhang et al, , 2006Bołdys and Okopień, 2009;Neumiller et al, 2010;Robinson et al, 2010). Because of their insulin-independent mechanism of action, SGLT2 inhibitors are associated with a low risk for hypoglycemia (Katsuno et al, 2007;Fujimori et al, 2008;Wilding et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Kalgutkar¹,

Tugnait²,

Zhu³

et al. 2011

Drug Metab Dispos

128

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C]metformin by PF-04971729 also were very weak (IC 50 ‫؍‬ ϳ900 M). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies after oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response.

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Indole-glucosides as novel sodium glucose co-transporter 2 (SGLT2) inhibitors. Part 2

Cited by 25 publications

References 16 publications

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Sergliflozin, a Novel Selective Inhibitor of Low-Affinity Sodium Glucose Cotransporter (SGLT2), Validates the Critical Role of SGLT2 in Renal Glucose Reabsorption and Modulates Plasma Glucose Level

Remogliflozin Etabonate, in a Novel Category of Selective Low-Affinity Sodium Glucose Cotransporter (SGLT2) Inhibitors, Exhibits Antidiabetic Efficacy in Rodent Models

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

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