Identification of Potent and Selective Cathepsin S Inhibitors Containing Different Central Cyclic Scaffolds
Identification of Potent and Selective Cathepsin S Inhibitors Containing Different Central Cyclic Scaffolds
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DOI：
10.1021/jm401528k
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发表时间：
2013-12-12
影响因子：
7.3
通讯作者：
Haap, Wolfgang
中科院分区：
文献类型：
--
作者：
Hilpert, Hans;Mauser, Harald;Haap, Wolfgang
从弱活性双重CatS/K抑制剂5开始，通过X射线分析支持的基于结构的设计，通过利用CatS的S2口袋中的特异性配体-受体相互作用，发现了有效和选择性（>50 000倍于CatK）的环戊烷衍生物22。将中心环戊烷支架改变为类似的吡咯烷衍生物57使酶以及基于细胞的活性分别显著降低了24倍和69倍。鉴定的最有希望的支架是容易获得的脯氨酸衍生物（例如，79）。该化合物具有0.47的吸引人的配体效率（LE），包括在CatS的Si和S3口袋中结合的另外的结构修饰，导致有利的体外和体内性质。化合物79以剂量依赖性方式减少抗原呈递的转基因D010.11小鼠模型中的IL-2产生，ED 50为5 mg/kg。
Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50 000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the Si and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.