J Med Chem. 2021 Feb 11;64(3):1725-1732. doi: 10.1021/acs.jmedchem.0c02112. Epub 2021 Feb 2.
A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound ) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound ) to animals following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound . In separate experiments, the prodrug demonstrated impressive tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures .
设计并合成了一种增强子结合蛋白 2（EZH2）抑制剂的吡啶酮磷酸前药，以提高抑制剂的水溶解度。对该前药（化合物 ）进行了药代动力学实验，以评估其在口服给药后将相应的母体化合物（化合物 ）递送到动物体内的能力。这些研究的结果表明，前药能够有效地转化为其母体化合物 。在单独的实验中，该前药在弥漫性大 B 细胞淋巴瘤 Karpas-422 细胞系衍生的异种移植模型中表现出令人印象深刻的肿瘤生长抑制作用。所描述的前药策略预计将普遍适用于溶解度差的含有吡啶酮的 EZH2 抑制剂，并为使此类化合物达到足够高的暴露水平提供了新的选择。
