Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.

中文翻译：

---

发现4-氨基-N -[（1 S）-1-（4-氯苯基）-3-羟丙基] -1-（7 H-吡咯并[2,3- d ]嘧啶-4-基）哌啶-4 -羧酰胺（AZD5363），一种口服生物利用性有效的Akt激酶抑制剂

对Akt具有ATP竞争性的吡咯并嘧啶抑制剂的类似物的广泛探索导致发现了临床候选药物AZD5363，该药物显示出增强的功效，降低的hERG亲和力以及对紧密相关的AGC激酶ROCK的更高选择性。该化合物表现出良好的临床前药物代谢和药代动力学（DMPK）特性，口服给药后，在体内Akt和下游生物标记的磷酸化作用上具有药效学抑制作用，并在乳腺癌异种移植模型中抑制了肿瘤的生长。