Pyrimidinopyrimidine inhibitors of ketohexokinase: exploring the ring C2 group that interacts with Asp-27B in the ligand binding pocket.
Inhibitors of ketohexokinase (KHK) have potential for the treatment of diabetes and obesity. We have continued studies on a pyrimidinopyrimidine series of potent KHK inhibitors by exploring the 2-position substituent (R(3)) that interacts with Asp-27B in the ATP-binding region of KHK (viz. 1, 2; Table 1). We found that increased spacing between the terminal ammonium group and the heterocyclic scaffold (viz. 16-20), such that interaction with Asp-27B is not possible, still results in potent KHK inhibition (IC(50)=15-50 nM). We propose a new interaction with Asp-194, which serves to expand the pyrimidinopyrimidine pharmacophore.
Janssen Pharmaceutical Companies of Johnson & Johnson, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. bmaryano@scripps.edu
Bruce E
BE
Maryanoff
John C
JC
O'Neill
David F
DF
McComsey
Stephen C
SC
Yabut
Diane K
DK
Luci
Alan C
AC
Gibbs
Margery A
MA
Connelly
D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005631:Fructokinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
D004791:Enzyme Inhibitors; D008024:Ligands; D011743:Pyrimidines; D005631:Fructokinases; C021475:ketohexokinase; C030986:pyrimidine