Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 19, Pages 7042-7051Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.05.037
Keywords
Glucokinase activator; Benzimidazole; Hypoglycemic; Type II diabetes
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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. (C) 2009 Published by Elsevier Ltd.
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