Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure-activity relationship study
Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure-activity relationship study
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新型四环苯并[b]咔唑酮作为高效且口服生物可利用的 ALK 抑制剂：设计、合成和构效关系研究
DOI：
10.1016/j.ejmech.2015.10.005
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发表时间：
2015
影响因子：
6.7
通讯作者：
Zhang A
中科院分区：
文献类型：
--
作者：
Jiang X;Zhou J;Ai J;Song Z;Peng X;Xing L;Xi Y;Guo J;Yao Q;Ding J;Geng M;Zhang A
在化合物5(alectinib，CH5424802)的基础上，通过在C8侧链上插入连接基或打开中间酮环，设计了四个具有更多可旋转键和更高分子柔韧性的四环苯并[b]咔唑酮类化合物。化合物15b被鉴定出对野生型和守门人突变的ALK激酶表现出几乎相同的高效力(3.4vs3.9nM)。该化合物具有良好的PK谱，大鼠口服生物利用度为67.1%。此外，化合物15b对ALK驱动的癌细胞和Karpas-299异种移植瘤模型显示出明显的生长抑制作用。
Four series of tetracyclic benzo[b]carbazolone compounds possessing more rotatable bonds and higher molecular flexibility were designed by either inserting a linker within the C8-side chain or by opening the middle ketone ring on the basis of compound5(Alectinib, CH5424802). Compound15bwas identified showing nearly identical high potency against both wild-type and the gatekeeper mutant ALK kinase (3.4 vs 3.9 nM). This compound has favorable PK profile with an oral bioavailability of 67.1% in rats. Moreover, compound15bshowed significant growth inhibition against ALK driven cancer cells and KARPAS-299 xenograft model.