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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,
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 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.
Molecular pharmacology 09/2011; 80(6):1156-65. · 4.53 Impact Factor
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Tomoharu Iino,
Yasuhiro Sasaki,
Makoto Bamba,
Morihiro Mitsuya,
Akio Ohno,
Kenji Kamata,
Hideka Hosaka,
Hiroko Maruki, Mayumi Futamura,
Riki Yoshimoto,
Sumika Ohyama,
Kaori Sasaki,
Masato Chiba,
Norikazu Ohtake,
Yasufumi Nagata,
Jun-Ichi Eiki,
Teruyuki Nishimura
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ABSTRACT: We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).
Bioorganic & medicinal chemistry letters 09/2009; 19(19):5531-8. · 2.65 Impact Factor
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Teruyuki Nishimura,
Tomoharu Iino,
Morihiro Mitsuya,
Makoto Bamba,
Hitomi Watanabe,
Daisuke Tsukahara,
Kenji Kamata,
Kaori Sasaki,
Sumika Ohyama,
Hideka Hosaka, Mayumi Futamura,
Yasufumi Nagata,
Jun-Ichi Eiki
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ABSTRACT: The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.
Bioorganic & medicinal chemistry letters 02/2009; 19(5):1357-60. · 2.65 Impact Factor
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ABSTRACT: Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V(max)) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRP-associated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.
Journal of Biological Chemistry 01/2007; 281(49):37668-74. · 4.77 Impact Factor
