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Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs

Eiki, Jun-Ichi ; Nagata, Yasufumi ; Futamura, Mayumi ; Sasaki-Yamamoto, Kaori ; Iino, Tomoharu ; Nishimura, Teruyuki ; Chiba, Masato ; Ohyama, Sumika ; Yoshida-Yoshimioto, Riki ; Fujii, Kenji ; Hosaka, Hideka ; Goto-Shimazaki, Hiroko ; Kadotani, Akito ; Ohe, Tomoyuki ; Lin, Songnian ; Langdon, Ronald B ; Berger, Joel P

Molecular pharmacology, December 2011, Vol.80(6), pp.1156-65 [Peer Reviewed Journal]

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  • Title:
    Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs
  • Author: Eiki, Jun-Ichi ; Nagata, Yasufumi ; Futamura, Mayumi ; Sasaki-Yamamoto, Kaori ; Iino, Tomoharu ; Nishimura, Teruyuki ; Chiba, Masato ; Ohyama, Sumika ; Yoshida-Yoshimioto, Riki ; Fujii, Kenji ; Hosaka, Hideka ; Goto-Shimazaki, Hiroko ; Kadotani, Akito ; Ohe, Tomoyuki ; Lin, Songnian ; Langdon, Ronald B ; Berger, Joel P
  • Description: 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 S(0.5) 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 EC(50) 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.
  • Is Part Of: Molecular pharmacology, December 2011, Vol.80(6), pp.1156-65
  • Identifier: E-ISSN: 1521-0111 ; PMID: 21937665 Version:1 ; DOI: 10.1124/mol.111.074401
  • Subjects: Disease Models, Animal ; Benzamides -- Pharmacokinetics ; Diabetes Mellitus, Type 2 -- Enzymology ; Glucokinase -- Metabolism ; Hypoglycemic Agents -- Pharmacokinetics ; Sulfones -- Pharmacokinetics
  • Language: English
  • Source: MEDLINE/PubMed (U.S. National Library of Medicine)

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