Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2009 Nov 1;19(21):6135-9. doi: 10.1016/j.bmcl.2009.09.013. Epub 2009 Sep 10.
Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50=80-420 nM) and imparted cellular potency (IC50=0.8-4.0 microM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50=10-30 nM) and sub-micromolar cellular potency (JY Ii IC50=200-720 nM).
基本的亲脂性取代基极大地提高了先前公开的一系列基于吡唑的芳基炔烃组织蛋白酶 S 抑制剂的细胞效力。在芳基炔烃的对位引入取代的苄胺可保持酶活性（hCatS IC50=80-420 nM）并赋予细胞效力（IC50=0.8-4.0 microM）。进一步优化药效团中环吗啉部分，可鉴定出对 CatS 具有更高亲和力的双环哌啶（IC50=10-30 nM），并具有亚微摩尔的细胞效力（JY Ii IC50=200-720 nM）。
