3imx

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3imx, resolution 2.00Å ()
Ligands: , ,
Gene: GCK, hCG_1745191, tcag7.801 (Homo sapiens)
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal Structure of human glucokinase in complex with a synthetic activator

Publication Abstract from PubMed

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-pip erazine-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.

Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes., Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao J, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang J, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, St Denny I, Taslimi PM, Vash B, Caplan SL, J Med Chem. 2009 Oct 8;52(19):6142-52. PMID:19746978

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

About this Structure

3imx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao J, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang J, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, St Denny I, Taslimi PM, Vash B, Caplan SL. Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes. J Med Chem. 2009 Oct 8;52(19):6142-52. PMID:19746978 doi:10.1021/jm900839k

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