Document Detail


Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.
MedLine Citation:
PMID:  19746978     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.
Authors:
Gregory R Bebernitz; Valerie Beaulieu; Bethany A Dale; Richard Deacon; Alokesh Duttaroy; Jiaping Gao; Melissa S Grondine; Ramesh C Gupta; Mesut Kakmak; Michael Kavana; Louise C Kirman; Jinsheng Liang; Wieslawa M Maniara; Siralee Munshi; Sunil S Nadkarni; Herbert F Schuster; Travis Stams; Irene St Denny; Paul M Taslimi; Brian Vash; Shari L Caplan
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-01     Completed Date:  2009-11-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6142-52     Citation Subset:  IM    
Affiliation:
Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts 02139, USA. greg.bebernitz@novartis.com
Data Bank Information
Bank Name/Acc. No.:
PDB/3IMX
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Glucose / drug effects
Diabetes Mellitus, Type 2 / drug therapy
Glucokinase / drug effects*
Glucose Tolerance Test
Hypoglycemic Agents / pharmacology
Liver / drug effects,  metabolism
Mice
Structure-Activity Relationship
Sulfonamides / pharmacology*,  therapeutic use
Chemical
Reg. No./Substance:
0/Blood Glucose; 0/Hypoglycemic Agents; 0/Sulfonamides; EC 2.7.1.2/Glucokinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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