AstraZeneca, Oncology Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):4163-8. doi: 10.1016/j.bmcl.2012.04.036. Epub 2012 Apr 13.
High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.
高通量筛选鉴定 mTOR 激酶抑制剂的方法揭示了磺酰基吗啉嘧啶 1 作为一个有吸引力的起点。该化合物具有良好的物理化学性质和对相关激酶（如 PI3Kα）的选择性。相关类似物的文库制备允许建立额外的 SAR 理解，特别是在苯环的 4 位上需要关键氢键供体模式的化合物，如吲哚 19。吲哚官能团的等排体替换导致鉴定出脲类化合物，如 32，它们在酶和细胞测定中均显示出良好的 mTOR 抑制水平。
