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Bioorg Med Chem Lett. 2012 Aug 15;22(16):5326-9. doi: 10.1016/j.bmcl.2012.06.008. Epub 2012 Jun 17.

Pyrimidinopyrimidine inhibitors of ketohexokinase: exploring the ring C2 group that interacts with Asp-27B in the ligand binding pocket.

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Janssen Pharmaceutical Companies of Johnson & Johnson, Welsh & McKean Roads, Spring House, PA 19477-0776, USA.


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.

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