The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators |
| |
Authors: | Keiji Takahashi Noriaki Hashimoto Chisato Nakama Kenji Kamata Kaori Sasaki Riki Yoshimoto Sumika Ohyama Hideka Hosaka Hiroko Maruki Yasufumi Nagata Jun-ichi Eiki Teruyuki Nishimura |
| |
Institution: | Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan |
| |
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. |
| |
Keywords: | |
本文献已被 ScienceDirect 等数据库收录! |
|