Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2
Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2
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DOI：
10.1021/jm501778s
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发表时间：
2015-03-12
影响因子：
7.3
通讯作者：
Pearson, Stuart E.
中科院分区：
文献类型：
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作者：
Pike, Kurt G.;Morris, Jeff;Pearson, Stuart E.
高通量筛选，随后进行先导产生活动，发现了一系列新的含脲的吗啉代嘧啶化合物，其作为mTORC 1和mTORC 2的有效和选择性双重抑制剂。我们描述了该系列的持续化合物优化活动，特别是专注于鉴定具有改善的细胞效价、改善的水溶性和在人肝细胞孵育中的良好稳定性的化合物。将来自经验SAR研究的知识与对晶格中分子相互作用的理解相结合，以改善细胞效力和溶解度，并使用LLE和pIC（50）-pSolubility的复合参数评估化合物质量和进展。采用预测模型来有效地挖掘确定的有吸引力的化学空间，从而发现42（AZD 3147），这是一种非常有效和选择性的mTORC 1和mTORC 2双重抑制剂，具有适合作为潜在临床候选药物开发的理化和药代动力学特性。
High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC(50)-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.