Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
J Med Chem. 2013 Mar 28;56(6):2196-206. doi: 10.1021/jm301706j. Epub 2013 Mar 15.
A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.
通过基于 rh-肾素活性位点对接和评分筛选器的企业化合物库的计算机相似性搜索，生成了一个包含天冬氨酸蛋白酶催化二联体假定识别基序的小片段文库。随后通过 NMR 筛选鉴定出低亲和力的命中化合物 3 和 4 为竞争性活性位点结合物，通过 X 射线晶体学可以证明它们与 rh-肾素的疏水性 S3-S1 口袋结合。作为平行多重命中发现方法的一部分，使用酶测定法通过 HTS 发现了 3,5-二取代哌啶（rac）-5。X 射线晶体学证明，外消旋体 (3S,5R)-5 是一种肽模拟抑制剂，与 rh-肾素原位点的非底物拓扑结构结合。描述了具有源自 3 的 P3(sp)-连接的三环 P3-P1 药效团的强效和选择性 (3S,5R)-12 的设计。(3S,5R)-12 在大鼠中具有口服生物利用度，并在双转基因大鼠模型中显示出降低血压的活性。
