嘧啶并嘧啶酮类酮己糖激酶抑制剂：探索与配体结合口袋中 Asp-27B 相互作用的环 C2 基团。
Pyrimidinopyrimidine inhibitors of ketohexokinase: exploring the ring C2 group that interacts with Asp-27B in the ligand binding pocket.
机构信息
Janssen Pharmaceutical Companies of Johnson & Johnson, Welsh & McKean Roads, Spring House, PA 19477-0776, USA.
出版信息
Bioorg Med Chem Lett. 2012 Aug 15;22(16):5326-9. doi: 10.1016/j.bmcl.2012.06.008. Epub 2012 Jun 17.
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.
酮己糖激酶（KHK）抑制剂具有治疗糖尿病和肥胖症的潜力。我们通过探索与 KHK 的 ATP 结合区域中的 Asp-27B 相互作用的 2-位取代基（R(3)）（即 1, 2；表 1），继续对嘧啶嘧啶系列强效 KHK 抑制剂进行了研究。我们发现，终端铵基团和杂环支架之间的间隔增大（即 16-20），使得与 Asp-27B 相互作用不可能，但仍能导致强效的 KHK 抑制（IC(50)=15-50 nM）。我们提出了与 Asp-194 的新相互作用，这有助于扩展嘧啶嘧啶药效团。
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