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Research ArticleEndocrine and Diabetes

KGA-2727, a Novel Selective Inhibitor of a High-Affinity Sodium Glucose Cotransporter (SGLT1), Exhibits Antidiabetic Efficacy in Rodent Models

Toshihide Shibazaki, Masaki Tomae, Yukiko Ishikawa-Takemura, Nobuhiko Fushimi, Fumiaki Itoh, Mitsuhiko Yamada and Masayuki Isaji
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 288-296; DOI: https://doi.org/10.1124/jpet.112.193045
Toshihide Shibazaki
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Masaki Tomae
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Yukiko Ishikawa-Takemura
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Nobuhiko Fushimi
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Fumiaki Itoh
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Mitsuhiko Yamada
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Masayuki Isaji
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Abstract

The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(β-d-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide (KGA-2727), which has a pyrazole-O-glucoside structure, as the first selective SGLT1 inhibitor. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. In a small intestine closed loop absorption test with normal rats, KGA-2727 inhibited the absorption of glucose but not that of fructose. After oral intake of starch along with KGA-2727 in normal rats, the residual content of glucose in the gastrointestinal tract increased. In the oral glucose tolerance test with streptozotocin-induced diabetic rats, KGA-2727 attenuated the elevation of plasma glucose after glucose loading, indicating that KGA-2727 improved postprandial hyperglycemia. In Zucker diabetic fatty (ZDF) rats, chronic treatments with KGA-2727 reduced the levels of plasma glucose and glycated hemoglobin. Furthermore, KGA-2727 preserved glucose-stimulated insulin secretion and reduced urinary glucose excretion with improved morphological changes of pancreatic islets and renal distal tubules in ZDF rats. In addition, the chronic treatment with KGA-2727 increased the level of glucagon-like peptide-1 in the portal vein. Taken together, our data indicate that the selective SGLT1 inhibitor KGA-2727 had antidiabetic efficacy and allow us to propose KGA-2727 as a candidate for a novel and useful antidiabetic agent.

Footnotes

  • This work was supported by the Kissei Pharmaceutical Co., Ltd.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.193045.

  • ABBREVIATIONS:

    SGLT1
    high-affinity sodium glucose cotransporter
    SGLT2
    low-affinity sodium glucose cotransporter
    AMG
    methyl-α-d-glucopyranoside
    AUC
    area under the curve
    Fib-I
    fibrosis index
    GHb
    glycated hemoglobin
    GIP
    glucose-dependent insulinotropic polypeptide
    GLP-1
    glucacon-like peptide-1
    GLUT5
    glucose transporter type 5
    Ins-I
    insulin index
    ZDF
    Zucker diabetic fatty
    KGA-2727
    3-(3-{4-[3-(β-d-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide
    T-1095A
    3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}phenyl)propan-1-one.

  • Received February 10, 2012.
  • Accepted April 23, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleEndocrine and Diabetes

SGLT1 Selective Inhibitor Has Antidiabetic Efficacy

Toshihide Shibazaki, Masaki Tomae, Yukiko Ishikawa-Takemura, Nobuhiko Fushimi, Fumiaki Itoh, Mitsuhiko Yamada and Masayuki Isaji
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 288-296; DOI: https://doi.org/10.1124/jpet.112.193045

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Research ArticleEndocrine and Diabetes

SGLT1 Selective Inhibitor Has Antidiabetic Efficacy

Toshihide Shibazaki, Masaki Tomae, Yukiko Ishikawa-Takemura, Nobuhiko Fushimi, Fumiaki Itoh, Mitsuhiko Yamada and Masayuki Isaji
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 288-296; DOI: https://doi.org/10.1124/jpet.112.193045
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