title: Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs.
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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co, Ltd, Tsukuba, Ibaraki, Japan. junichi_eiki@merck.com
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Eiki
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Nagata
authors.forename: Mayumi
authors.initials: M
authors.lastname: Futamura
authors.forename: Kaori
authors.initials: K
authors.lastname: Sasaki-Yamamoto
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Iino
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Nishimura
authors.forename: Masato
authors.initials: M
authors.lastname: Chiba
authors.forename: Sumika
authors.initials: S
authors.lastname: Ohyama
authors.forename: Riki
authors.initials: R
authors.lastname: Yoshida-Yoshimioto
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujii
authors.forename: Hideka
authors.initials: H
authors.lastname: Hosaka
authors.forename: Hiroko
authors.initials: H
authors.lastname: Goto-Shimazaki
authors.forename: Akito
authors.initials: A
authors.lastname: Kadotani
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.forename: Songnian
authors.initials: S
authors.lastname: Lin
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Langdon
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics* / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology*; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013450:Sulfones / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C569222:3-((6-(ethylsulfonyl)-3-pyridinyl)oxy)-5-(2-hydroxy-1-methylethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide; D001549:Benzamides; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013450:Sulfones; D005941:Glucokinase