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 (IC50 = 15-50 nM). We propose a new interaction with Asp-194, which serves to expand the pyrimidinopyrimidine pharmacophore.
Maryanoff, Bruce E.,O'Neill, John C.,McComsey, David F.,Yabut, Stephen C.,Luci, Diane K.,Gibbs, Alan C.,Connelly, Margery A.
scheme or table
p. 5326 - 5329
(2012/09/07)
Inhibitors of ketohexokinase: Discovery of pyrimidinopyrimidines with specific substitution that complements the ATP-binding site
Attenuation of fructose metabolism by the inhibition of ketohexokinase (KHK; fructokinase) should reduce body weight, free fatty acids, and triglycerides, thereby offering a novel approach to treat diabetes and obesity in response to modern diets. We have
Maryanoff, Bruce E.,O'Neill, John C.,McComsey, David F.,Yabut, Stephen C.,Luci, Diane K.,Jordan Jr., Alfonzo D.,Masucci, John A.,Jones, William J.,Abad, Marta C.,Gibbs, Alan C.,Petrounia, Ioanna
p. 538 - 543
(2011/09/15)
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