Hutchison MediPharma Limited , Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park , Shanghai 201203 , China.
Janssen Pharmaceuticals Research & Development , 3210 Merryfield Row , San Diego , California 92121 , United States.
J Med Chem. 2019 May 23;62(10):4936-4948. doi: 10.1021/acs.jmedchem.8b02014. Epub 2019 May 8.
An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
建立了一个电子密度模型，并将其用于鉴定新型吡咯并三嗪酮取代喹唑啉酮，这是一种常用的部分，可赋予PI3Kγ和PI3Kδ抑制剂选择性。在分子对接的指导下，然后使用新型环状部分将这个新的特异性片段连接到抑制剂的铰链结合区域。进一步围绕铰链区域进行结构-活性关系优化，导致发现候选物 26，这是一种高度有效和选择性的 PI3Kγ-PI3Kδ 双重抑制剂，在临床前物种中具有良好的药物代谢和药代动力学特性。
