2ati: Difference between revisions
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==Overview== | ==Overview== | ||
Using a focused screening approach, acyl ureas have been discovered as a | 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. | ||
==Disease== | ==Disease== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Brachvogel, V.]] | [[Category: Brachvogel, V.]] | ||
[[Category: Burger, H | [[Category: Burger, H J.]] | ||
[[Category: Defossa, E.]] | [[Category: Defossa, E.]] | ||
[[Category: Herling, A | [[Category: Herling, A W.]] | ||
[[Category: Kadereit, D.]] | [[Category: Kadereit, D.]] | ||
[[Category: Klabunde, T.]] | [[Category: Klabunde, T.]] | ||
[[Category: Oikonomakos, N | [[Category: Oikonomakos, N G.]] | ||
[[Category: Roedern, E | [[Category: Roedern, E von.]] | ||
[[Category: Sarubbi, E.]] | [[Category: Sarubbi, E.]] | ||
[[Category: Schmoll, D.]] | [[Category: Schmoll, D.]] | ||
[[Category: Schoenafinger, K.]] | [[Category: Schoenafinger, K.]] | ||
[[Category: Wendt, K | [[Category: Wendt, K U.]] | ||
[[Category: GLC]] | [[Category: GLC]] | ||
[[Category: IHU]] | [[Category: IHU]] | ||
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[[Category: glycogen phosphorylase]] | [[Category: glycogen phosphorylase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:30:55 2008'' | ||
Revision as of 17:30, 21 February 2008
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Glycogen Phosphorylase Inhibitors
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Glycogen storage disease VI OMIM:[232700]
About this StructureAbout this Structure
2ATI is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
ReferenceReference
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
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