Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus

Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC₅₀ of 70nM. YH-GKA showed similar glucose AUC reduc...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (2), p.537-542
Main Authors: Park, Kaapjoo, Lee, Byoung Moon, Kim, Young Hwan, Han, Taedong, Yi, Wonhui, Lee, Dong Hoon, Choi, Hyun Ho, Chong, Wonee, Lee, Chun Ho
Format: Article
Language:English
Subjects:
adverse effects
Animal models
Animals
Benzamides - chemical synthesis
Benzamides - chemistry
Benzamides - pharmacology
Benzamides - therapeutic use
Bioavailability
Blood
blood glucose
blood lipids
Body weight
Cells, Cultured
chemistry
Diabetes mellitus
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - enzymology
Drug Discovery
Enzyme Activation - drug effects
Glucokinase
Glucokinase - metabolism
Glucose
Humans
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacology
Hypoglycemic Agents - therapeutic use
in vitro studies
Metformin
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Structure
noninsulin-dependent diabetes mellitus
Phenethylamines - chemical synthesis
Phenethylamines - chemistry
Phenethylamines - pharmacology
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacology
Pyridines - therapeutic use
Serum lipids
Side effects
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Summary:Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC₅₀ of 70nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.11.018