Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.

中文翻译：

---

发现 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides 作为蛋白激酶 B (Akt) 的选择性口服活性抑制剂

蛋白激酶 B（PKB 或 Akt）是调节生长和存活的细胞内信号通路的重要组成部分。通过 PKB 的信号传导在癌症中经常失调，因此 PKB 抑制剂具有作为抗肿瘤剂的潜力。一系列 4-benzyl-1-(7 H -pyrrolo[2,3 - d ]pyrimidin-4-yl)piperidin-4- amines中亲脂取代的优化提供了 ATP 竞争性的纳摩尔抑制剂，具有高达 150-与密切相关的激酶 PKA 相比，PKB 抑制的选择性倍数。尽管在细胞检测中具有活性，但含有 4-amino-4-benzylpiperidines 的化合物在体内进行代谢，导致快速清除和低口服生物利用度。哌啶和亲脂取代基之间的连接基团的变化鉴定了 4-amino-1-(7H -pyrrolo[2,3 - d ]pyrimidin-4-yl)piperidine-4-carboxamides 作为 PKB 的有效和口服生物可利用的抑制剂。代表性化合物在体内通过 PKB 调节信号传导的生物标志物，并在耐受良好的剂量下强烈抑制裸鼠中人类肿瘤异种移植物的生长。