title: Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes.
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.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Scientific and Medical Affairs, D-65926 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klabunde
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Wendt
authors.forename: Dieter
authors.initials: D
authors.lastname: Kadereit
authors.forename: Volker
authors.initials: V
authors.lastname: Brachvogel
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Burger
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Herling
authors.forename: Nikos G
authors.initials: NG
authors.lastname: Oikonomakos
authors.forename: Magda N
authors.initials: MN
authors.lastname: Kosmopoulou
authors.forename: Dieter
authors.initials: D
authors.lastname: Schmoll
authors.forename: Edoardo
authors.initials: E
authors.lastname: Sarubbi
authors.forename: Erich
authors.initials: E
authors.lastname: von Roedern
authors.forename: Karl
authors.initials: K
authors.lastname: Schönafinger
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Defossa
mesh_terms: D000249:Adenosine Monophosphate / Q000737:chemistry; D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors* / Q000737:chemistry; D024982:Glycogen Phosphorylase, Muscle Form / Q000737:chemistry; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D051381:Rats; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000249:Adenosine Monophosphate; D014508:Urea; D025001:Glycogen Phosphorylase, Liver Form; D024982:Glycogen Phosphorylase, Muscle Form