Na+-Glucose Cotransporter Inhibitors as Antidiabetics. I. Synthesis and Pharmacological Properties of 4'-Dehydroxyphlorizin Derivatives Based on a New Concept.

Tsujihara, Kenji; Hongu, Mitsuya; Saito, Kunio; Inamasu, Masanori; Akita, Keiichi; Oku, Akira; Matsumoto, Mamoru

doi:10.1248/cpb.44.1174

Cited by 84 publications

(65 citation statements)

References 1 publication

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“…Phloridzin has been applied as a selective SGLT inhibitor, 27) although the activity is known to have been lost during hydrolysis to release intramolecular glucose residues by digestive enzymes in the small intestine. 28,29) If the molecule were to be protected from enzymatic decomposition, its inhibitory activity against glucose absorption could be expected to remain relatively longer without any loss of activity. Many kinds of the Cglycoside type of phloridzin, 30,31) phloretin (the aglycon portion of phloridzin) derivatives, 32) and the polymer type of phloridzin 33) have been examined for application to developing a new SGLT inhibitor providing resistance to decomposition.…”

Section: Discussionmentioning

confidence: 99%

Suppressive Effect of Peach Leaf Extract on Glucose Absorption from the Small Intestine of Mice

Shirosaki

Koyama

Yazawa

2012

Bioscience, Biotechnology, and Biochemistry

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Section: Discussionmentioning

confidence: 99%

Suppressive Effect of Peach Leaf Extract on Glucose Absorption from the Small Intestine of Mice

Shirosaki

Koyama

Yazawa

2012

Bioscience, Biotechnology, and Biochemistry

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“…SGLT1 and GLUT2, which exist not only in the intestinal epithelial (Coady et al, 1990;Lee et al, 1994), have been considered potential targets of drug development for glycemic control in diabetes (Asano et al, 2004). Phlorizin and its derivatives including T-1095 [3-(benzo[b]furan-5-yl)-2Ј,6Ј-dihydroxy-4Ј-methylpropiophenone 2Ј-O-(6-O-methoxycarbonyl-␤-D-glycopyranoside)], p-azidobenzylphlorizin, 4-azidophlorizin, and a series of 4Ј-dehydroxyphlorizin derivatives have been tested for their antihyperglycemic effects as SGLT1 inhibitors (Gibbs et al, 1982;Wyse et al, 1989;Tsujihara et al, 1996;Oku et al, 1999). Many studies have shown that phlorizin could normalize hyperglycemia by subcutaneous injection or infusion into diabetic animals (Janssen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Desoxyrhaponticin (3,5-Dihydroxy-4′-methoxystilbene 3-O-β-d-glucoside) Inhibits Glucose Uptake in the Intestine and Kidney: In Vitro and in Vivo Studies

Li¹,

Tao²,

Lau³

et al. 2006

J Pharmacol Exp Ther

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Rhubarb extracts have been reported to improve oral glucose tolerance in diabetic animals. In the present study we have investigated the antidiabetic actions of desoxyrhaponticin, a major stilbene in rhubarb, as a glucose uptake inhibitor. Desoxyrhaponticin was demonstrated to inhibit glucose uptake in rabbit intestinal membrane vesicles as well as in rat everted gut sleeves, with IC 50 values of 148.3 and 30.9 M, respectively. Kinetics studies revealed that desoxyrhaponticin is a competitive inhibitor of glucose uptake in both systems. Moreover, desoxyrhaponticin could reduce glucose uptake in the intestinal membrane vesicles of both normal and diabetic rats. In addition, glucose uptake in the renal membrane vesicles of both normal and diabetic rats was reduced by desoxyrhaponticin. Under the inhibition of desoxyrhaponticin, uptake of glucose in both the intestinal and renal membrane vesicles of the normal rats was no different from that of the diabetic rats. The IC 50 values of the uptake inhibition in the renal membrane vesicles of normal and diabetic rats were 118.8 and 115.7 M, respectively. In a type 2 diabetic animal model in which rats have been treated with streptozotocin at the neonatal stage, postprandial hyperglycemia was significantly suppressed by oral administration of this compound (300 mg/kg b.wt.). These results suggest that desoxyrhaponticin is an agent that is potentially effective in controlling postprandial hyperglycemia in diabetes. The in vivo antidiabetic action of this compound can be explained, in part at least, by inhibition of glucose transport in the small intestine and inhibition of glucose reabsorption in the kidney.

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“…Glucose uptake in erythrocytes was measured by the method of Tsujihara, with minor modifications (Tsujihara et al, 1996). First, 10 ml of human blood and 40 ml of ice-cold Dulbecco's phosphate-buffered saline (D-PBS) (Sigma-Aldrich) were gently mixed.…”

Section: Chemicalsmentioning

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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Na+-Glucose Cotransporter Inhibitors as Antidiabetics. I. Synthesis and Pharmacological Properties of 4'-Dehydroxyphlorizin Derivatives Based on a New Concept.

Cited by 84 publications

References 1 publication

Suppressive Effect of Peach Leaf Extract on Glucose Absorption from the Small Intestine of Mice

Suppressive Effect of Peach Leaf Extract on Glucose Absorption from the Small Intestine of Mice

Desoxyrhaponticin (3,5-Dihydroxy-4′-methoxystilbene 3-O-β-d-glucoside) Inhibits Glucose Uptake in the Intestine and Kidney: In Vitro and in Vivo Studies

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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