Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes.
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.
Klabunde
Thomas
T
Sanofi-Aventis Deutschland GmbH, Scientific and Medical Affairs, D-65926 Frankfurt am Main, Germany.
Wendt
K Ulrich
KU
Kadereit
Dieter
D
Brachvogel
Volker
V
Burger
Hans-Jörg
HJ
Herling
Andreas W
AW
Oikonomakos
Nikos G
NG
Kosmopoulou
Magda N
MN
Schmoll
Dieter
D
Sarubbi
Edoardo
E
von Roedern
Erich
E
Schönafinger
Karl
K
Defossa
Elisabeth
E
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
D000249:Adenosine Monophosphate; D014508:Urea; D025001:Glycogen Phosphorylase, Liver Form; D024982:Glycogen Phosphorylase, Muscle Form