The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators.
The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole. The activator exhibited good PK profiles in rats and dogs, and significant hypoglycemic efficacy at 1 mg/kg po dosing in a rat OGTT model. The binding site and binding mode of the benzimidazole class of GKA with GK protein was confirmed by X-ray crystallographic analysis.
Takahashi
Keiji
K
Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. g94e079@ruri.waseda.jp
Hashimoto
Noriaki
N
Nakama
Chisato
C
Kamata
Kenji
K
Sasaki
Kaori
K
Yoshimoto
Riki
R
Ohyama
Sumika
S
Hosaka
Hideka
H
Maruki
Hiroko
H
Nagata
Yasufumi
Y
Eiki
Jun-ichi
J
Nishimura
Teruyuki
T
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D005941:Glucokinase / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis; D051381:Rats
D001562:Benzimidazoles; D007004:Hypoglycemic Agents; D005941:Glucokinase