We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (K_i = 22.4 μM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.

中文翻译：

---

通过基于片段的药物设计鉴定磷酸二酯酶2抑制的新的铅类

我们已经使用基于片段的筛选确定了一种新型的PDE2抑制剂系列。吡唑并嘧啶片段1具有很弱的效价（K _i  = 22.4μM），但表现出良好的结合效率（LBE = 0.49，LLE = 4.48），可以作为基于结构的药物设计的起点。借助分子建模和X射线晶体学，该片段被开发为一系列具有良好理化性质的有效PDE2抑制剂。鉴定出表现出有利的大鼠药代动力学性质的化合物16（一种PDE2选择性抑制剂）。