Zhang Wenqiang, Zhou Xiaoyu, Zhu Hao, Fan Yawen, Chen Zhuolin, Wang Chenxiao, Chen Xingru, Li Hongmei, Lu Tao, Wei Xian, Chen Yadong, Chen Caiping, Jiao Yu
School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198 China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009 China.
Bioorg Med Chem. 2025 Apr 1;120:118082. doi: 10.1016/j.bmc.2025.118082. Epub 2025 Jan 27.
We report herein the development of a series of novel AR antagonists characterized by a spirocyclic scaffold, employing scaffold hopping and structure-based drug design strategies. Most of the spirocyclic derivatives exhibited enhanced AR antagonistic activity and superior antiproliferative activity against LNCaP cells compared to enzalutamide. Among them, compound 21 demonstrated moderate antiproliferative activity against enzalutamide resistant prostate cancer cell lines and exhibited favorable in vitro metabolic stability. These findings offer valuable insights for the rational design of AR antagonists for the treatment of advanced prostate cancer.
我们在此报告了一系列以螺环骨架为特征的新型雄激素受体（AR）拮抗剂的研发情况，采用了骨架跃迁和基于结构的药物设计策略。与恩杂鲁胺相比，大多数螺环衍生物表现出增强的AR拮抗活性以及对LNCaP细胞更强的抗增殖活性。其中，化合物21对恩杂鲁胺耐药的前列腺癌细胞系表现出中等抗增殖活性，并具有良好的体外代谢稳定性。这些发现为合理设计用于治疗晚期前列腺癌的AR拮抗剂提供了有价值的见解。
