Medicinal Research Laboratories, ‡Drug Developmental Research Laboratories, and §Innovative Drug Discovery Research Laboratories, Shionogi Pharmaceutical Research Center , 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
J Med Chem. 2015 Feb 26;58(4):1760-75. doi: 10.1021/jm501599u. Epub 2015 Feb 10.
Monopolar spindle 1 (Mps1) is an attractive oncology target due to its high expression level in cancer cells as well as the correlation of its expression levels with histological grades of cancers. An imidazo[1,2-a]pyrazine 10a was identified during an HTS campaign. Although 10a exhibited good biochemical activity, its moderate cellular as well as antiproliferative activities needed to be improved. The cocrystal structure of an analogue of 10a guided our lead optimization to introduce substituents at the 6-position of the scaffold, giving the 6-aryl substituted 21b which had improved cellular activity but no oral bioavailability in rat. Property-based optimization at the 6-position and a scaffold change led to the discovery of the imidazo[1,2-b]pyridazine-based 27f, an extremely potent (cellular Mps1 IC50 = 0.70 nM, A549 IC50 = 6.0 nM), selective Mps1 inhibitor over 192 kinases, which could be orally administered and was active in vivo. This 27f demonstrated remarkable antiproliferative activity in the nanomolar range against various tissue cancer cell lines.
由于其在癌细胞中的高表达水平以及其表达水平与癌症组织学分级的相关性，单极纺锤体 1（Mps1）是一个有吸引力的肿瘤学靶点。在高通量筛选（HTS）活动中鉴定出了一种咪唑并[1,2-a]吡嗪 10a。尽管 10a 表现出良好的生化活性，但仍需要提高其细胞活性和抗增殖活性。类似物的共晶结构指导了我们的先导化合物优化，在支架的 6 位引入取代基，得到了 6-芳基取代的 21b，其细胞活性得到了改善，但在大鼠中没有口服生物利用度。基于性质的 6 位优化和支架变化导致发现了基于咪唑并[1,2-b]哒嗪的 27f，这是一种极其有效的（细胞 Mps1 IC50=0.70 nM，A549 IC50=6.0 nM）、选择性 Mps1 抑制剂，对 192 种激酶具有选择性，可口服给药并在体内具有活性。27f 在纳摩尔范围内对各种组织癌细胞系表现出显著的抗增殖活性。
