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Research ArticleArticle

Pharmacokinetic and Pharmacodynamic Properties of the Glucokinase Activator MK-0941 in Rodent Models of Type 2 Diabetes and Healthy Dogs

Jun-ichi Eiki, Yasufumi Nagata, Mayumi Futamura, Kaori Sasaki-Yamamoto, Tomoharu Iino, Teruyuki Nishimura, Masato Chiba, Sumika Ohyama, Riki Yoshida-Yoshimioto, Kenji Fujii, Hideka Hosaka, Hiroko Goto-Shimazaki, Akito Kadotani, Tomoyuki Ohe, Songnian Lin, Ronald B. Langdon and Joel P. Berger
Molecular Pharmacology December 2011, 80 (6) 1156-1165; DOI: https://doi.org/10.1124/mol.111.074401
Jun-ichi Eiki
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Yasufumi Nagata
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Mayumi Futamura
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Kaori Sasaki-Yamamoto
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Tomoharu Iino
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Teruyuki Nishimura
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Masato Chiba
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Sumika Ohyama
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Riki Yoshida-Yoshimioto
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Kenji Fujii
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Hideka Hosaka
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Hiroko Goto-Shimazaki
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Akito Kadotani
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Tomoyuki Ohe
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Songnian Lin
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Ronald B. Langdon
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Joel P. Berger
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Abstract

Glucokinase activators (GKAs) are small-molecule agents that enhance glucose sensing by pancreatic β cells and glucose metabolism by hepatocytes. There is strong interest in these agents as potential therapies for type 2 diabetes. Here, we report key pharmacokinetic and pharmacodynamic findings from preclinical studies of the GKA 3-[[6-(ethylsulfonyl)-3-pyridinyl]oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (MK-0941). Incubated in vitro with recombinant human glucokinase, 1 μM MK-0941 lowered the S0.5 of this enzyme for glucose from 6.9 to 1.4 mM and increased the maximum velocity of glucose phosphorylation by 1.5-fold. In 2.5 and 10 mM glucose, the EC50 values for activation of GK by MK-0941 were 0.240 and 0.065 μM, respectively. Treatment of isolated rat islets of Langerhans and hepatocytes with 10 μM MK-0941 increased insulin secretion by 17-fold and glucose uptake up to 18-fold, respectively. MK-0941 exhibited strong glucose-lowering activity in C57BL/6J mice maintained on a high-fat diet (HFD), db/db mice, HFD plus low-dose streptozotocin-treated mice, and nondiabetic dogs. In both mice and dogs, oral doses of MK-0941 were rapidly absorbed and rapidly cleared from the blood; plasma levels reached maximum within 1 h and fell thereafter with a half-life of ∼2 h. During oral glucose tolerance testing in dogs, MK-0941 reduced total area-under-the-curve postchallenge (0–2 h) plasma glucose levels by up to 48% compared with vehicle-treated controls. When administered twice daily to mice for 16 days, and once daily to the dog for 4 days, MK-0941 remained efficacious on successive days. These findings support further investigation of MK-0941 as a potential therapeutic agent for treatment of type 2 diabetes.

Footnotes

  • This research was supported by Merck, Sharp, and Dohme, Inc.

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

    doi:10.1124/mol.111.074401.

  • ABBREVIATIONS:

    GKA
    glucokinase activator
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    MK-0941
    3-[[6-(ethylsulfonyl)-3-pyridinyl]oxy]-5-[(1S)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide
    HFD
    high-fat diet
    HK
    hexokinase
    DMSO
    dimethyl sulfoxide
    T-NAD
    thio-NAD
    ELISA
    enzyme-linked immunosorbent assay
    HbA1c
    glycated hemoglobin
    3-HBA
    3-hydroxybutyric acid
    OGTT
    oral glucose tolerance test
    compound B
    3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-yl benzamide
    STZ
    streptozotocin.

  • Received June 29, 2011.
  • Accepted September 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (6)
Molecular Pharmacology
Vol. 80, Issue 6
1 Dec 2011
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Research ArticleArticle

Preclinical PK/PD of the Glucokinase Activator MK-0941

Jun-ichi Eiki, Yasufumi Nagata, Mayumi Futamura, Kaori Sasaki-Yamamoto, Tomoharu Iino, Teruyuki Nishimura, Masato Chiba, Sumika Ohyama, Riki Yoshida-Yoshimioto, Kenji Fujii, Hideka Hosaka, Hiroko Goto-Shimazaki, Akito Kadotani, Tomoyuki Ohe, Songnian Lin, Ronald B. Langdon and Joel P. Berger
Molecular Pharmacology December 1, 2011, 80 (6) 1156-1165; DOI: https://doi.org/10.1124/mol.111.074401

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Research ArticleArticle

Preclinical PK/PD of the Glucokinase Activator MK-0941

Jun-ichi Eiki, Yasufumi Nagata, Mayumi Futamura, Kaori Sasaki-Yamamoto, Tomoharu Iino, Teruyuki Nishimura, Masato Chiba, Sumika Ohyama, Riki Yoshida-Yoshimioto, Kenji Fujii, Hideka Hosaka, Hiroko Goto-Shimazaki, Akito Kadotani, Tomoyuki Ohe, Songnian Lin, Ronald B. Langdon and Joel P. Berger
Molecular Pharmacology December 1, 2011, 80 (6) 1156-1165; DOI: https://doi.org/10.1124/mol.111.074401
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