Wei Jianmei, Pio Barbara A, Cai Hui, Meduna Steven P, Sun Siquan, Gu Yin, Jiang Wen, Thurmond Robin L, Karlsson Lars, Edwards James P
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2007 Oct 15;17(20):5525-8. doi: 10.1016/j.bmcl.2007.08.038. Epub 2007 Aug 22.
High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
通过对早期人组织蛋白酶S（CatS）抑制剂系列中发现的苯并稠合五元环杂环进行修饰，开发出了高效的基于吡唑的人组织蛋白酶S非共价抑制剂。尽管该杂环骨架上的取代对酶活性有适度影响，但对细胞活性却观察到显著效果。优化得到了吲哚和苯并噻吩衍生的类似物，它们是高亲和力的组织蛋白酶S抑制剂（IC(50)=20 - 40 nM），具有良好的细胞活性（IC(50)=30 - 340 nM）。
