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.