Oncology IMED Biotech Unit , AstraZeneca, R&D Boston , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.
J Med Chem. 2019 Feb 14;62(3):1593-1608. doi: 10.1021/acs.jmedchem.8b01837. Epub 2019 Jan 30.
Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.
在此，我们报告了一系列三环吲唑的鉴定和合成，它们是一类新型的选择性雌激素受体降解剂拮抗剂。用吲唑基团取代我们之前报道的四氢异喹啉骨架中存在的酚，导致在体外谷胱甘肽捕获试验中消除了一个反应性代谢物信号。进一步的优化，通过 X 射线晶体结构和 NMR 构象研究指导，改变了烷基侧链和取代的芳基基团，得到了在人肝细胞中低转化率和增强化学稳定性的化合物。化合物 9 作为该系列的代表进行了药理学研究，表现出理想的雌激素受体α降解剂拮抗剂特性，并在乳腺癌的异种移植模型中表现出活性。
