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 (R3) 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.

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