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2ati
From Proteopedia
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[[Image:2ati.gif|left|200px]] | [[Image:2ati.gif|left|200px]] | ||
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'''Glycogen Phosphorylase Inhibitors''' | '''Glycogen Phosphorylase Inhibitors''' | ||
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[[Category: Schoenafinger, K.]] | [[Category: Schoenafinger, K.]] | ||
[[Category: Wendt, K U.]] | [[Category: Wendt, K U.]] | ||
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Revision as of 16:27, 3 May 2008
Glycogen Phosphorylase Inhibitors
Overview
Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.
About this Structure
2ATI is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes., Klabunde T, Wendt KU, Kadereit D, Brachvogel V, Burger HJ, Herling AW, Oikonomakos NG, Kosmopoulou MN, Schmoll D, Sarubbi E, von Roedern E, Schonafinger K, Defossa E, J Med Chem. 2005 Oct 6;48(20):6178-93. PMID:16190745 Page seeded by OCA on Sat May 3 19:27:26 2008
