477343-25-2Relevant articles and documents
Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes
Klabunde, Thomas,Wendt, K. Ulrich,Kadereit, Dieter,Brachvogel, Volker,Burger, Hans-J?rg,Herling, Andreas W.,Oikonomakos, Nikos G.,Kosmopoulou, Magda N.,Schmoll, Dieter,Sarubbi, Edoardo,Von Roedern, Erich,Sch?nafinger, Karl,Defossa, Elisabeth
, p. 6178 - 6193 (2007/10/03)
Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hiGPa). The X-ray structure of screening hit 1 (IC50 = 2 μM) 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 μM). 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 A? 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.
