2ATI

Glycogen Phosphorylase Inhibitors

Summary for 2ATI

• Entry DOI: 10.2210/pdb2ati/pdb
• Related: 1WUT 1WUY 1WV0 1WV1
• Descriptor: Glycogen phosphorylase, liver form, alpha-D-glucopyranose, N-(2-CHLORO-4-FLUOROBENZOYL)-N'-(5-HYDROXY-2-METHOXYPHENYL)UREA, ... (5 entities in total)
• Functional Keywords: glycogen phosphorylase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 195822.56

Authors

Klabunde, T.,Wendt, K.U.,Kadereit, D.,Brachvogel, V.,Burger, H.J.,Herling, A.W.,Oikonomakos, N.G.,Schmoll, D.,Sarubbi, E.,von Roedern, E.,Schoenafinger, K.,Defossa, E. (deposition date: 2005-08-25, release date: 2006-08-25, Last modification date: 2025-03-26)

Primary citation

Klabunde, T.,Wendt, K.U.,Kadereit, D.,Brachvogel, V.,Burger, H.J.,Herling, A.W.,Oikonomakos, N.G.,Kosmopoulou, M.N.,Schmoll, D.,Sarubbi, E.,von Roedern, E.,Defossa, E.
Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes.
J.Med.Chem., 48:6178-6193, 2005

PubMed Abstract: 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.

PubMed: 16190745
DOI: 10.1021/jm049034y

Experimental method

X-RAY DIFFRACTION (1.9 Å)