title: The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators.
abstract: 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.
authors.affiliation: Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. g94e079@ruri.waseda.jp
authors.forename: Keiji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Chisato
authors.initials: C
authors.lastname: Nakama
authors.forename: Kenji
authors.initials: K
authors.lastname: Kamata
authors.forename: Kaori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Riki
authors.initials: R
authors.lastname: Yoshimoto
authors.forename: Sumika
authors.initials: S
authors.lastname: Ohyama
authors.forename: Hideka
authors.initials: H
authors.lastname: Hosaka
authors.forename: Hiroko
authors.initials: H
authors.lastname: Maruki
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Nagata
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Eiki
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Nishimura
mesh_terms: 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
chemical_list: D001562:Benzimidazoles; D007004:Hypoglycemic Agents; D005941:Glucokinase