Heteroaryl-O-glucosides as novel sodium glucose co-transporter 2 inhibitors. Part 1

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

doi:10.1016/j.bmcl.2005.08.067

Cited by 31 publications

(11 citation statements)

References 19 publications

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“…Selective suppression of SGLT2 activity by small molecule inhibitors increases excretion of glucose from the body (via inhibition of renal glucose reabsorption) and assists in the reduction of hyperglycemia in T2DM (Oku et al, 1999;Adachi et al, 2000;Zhang et al, 2005;Bołdys and Okopie n 2009;Neumiller et al, 2010). Because of their ability to increase urinary glucose excretion in T2DM, SGLT2 inhibitors offer the advantage of plasma glucose-lowering without inducing excessive insulin secretion (Katsuno et al, 2007;Fujimori et al, 2008;Wilding et al, 2009;Patel and Fonseca, 2010).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

et al. 2012

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The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [ 14 C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of ertugliflozin in humans was rapid with a T max at ∼1.0 hour. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for ∼35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (∼39.3% of the dose in urine), of which M4c was the major regioisomer (∼31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-b-and -3-O-b-glucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl ertugliflozin (M2), which accounted for ∼5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-b-(M4a) and 3-O-b-(M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

et al. 2012

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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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“…Phloretin, the aglycon of phlorizin, is produced as a metabolite and may inhibit facilitative glucose transporter (GLUT1), which is responsible for glucose uptake in various tissues (Wheeler and Hinkle, 1981;Ehrenkranz et al, 2005). Several researchers have focused on the renal glucose reabsorption system as a way of improving hyperglycemia in type 2 diabetes mellitus, and SGLT inhibitors have been developed (Kees et al, 1996;Oku et al, 1999;Link and Sorensen, 2000;Ohsumi et al, 2003, Zhang et al, 2005. Several types of oral hypoglycemic drug are available for the clinical control of blood glucose (DeFronzo, 1999).…”

mentioning

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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Heteroaryl-O-glucosides as novel sodium glucose co-transporter 2 inhibitors. Part 1

Cited by 31 publications

References 19 publications

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

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

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

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