The androgen receptor (AR) antagonists are efficient therapeutics for the treatment of prostate cancer (PCa). All the approved AR antagonists to date are targeted to the ligand-binding pocket (LBP) of AR and have suffered from various drug resistances, whereas AR antagonist targeting non-LBP site of AR is conceived as a promising strategy. Through the scaffold hopping of AR LBP antagonists, the 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile was designed as a new core structure for AR antagonists. A total of 46 compounds were synthesized and biologically evaluated to disclose compounds 2f, 2k, and 4c, exhibiting potent AR antagonistic activities (IC₅₀ up to 69 nM), force against antiandrogen resistance, and untraditional targeting site of probably AR binding function 3. Therein, 4c exhibited effective tumor growth inhibition in LNCaP xenograft study upon oral administration. This work provides a novel chemical scaffold for AR antagonists and offers new perspective for the development of PCa therapy.

中文翻译：

---

发现 2-(1-(3-Chloro-4-cyanophenyl)-1H-pyrazol-3-yl)acetamides 作为针对雄激素受体的有效、选择性和口服拮抗剂

雄激素受体 (AR) 拮抗剂是治疗前列腺癌 (PCa) 的有效疗法。迄今为止，所有已批准的 AR 拮抗剂均针对 AR 的配体结合袋 (LBP)，并且具有各种耐药性，而针对 AR 的非 LBP 位点的 AR 拮抗剂被认为是一种有前途的策略。通过AR LBP拮抗剂的支架跳跃，2-氯-4-(1 H-吡唑-1-基)苄腈被设计为AR拮抗剂的新核心结构。共合成了 46 种化合物，并对其进行了生物学评估，揭示了化合物2f、2k和4c，它们表现出有效的 AR 拮抗活性（IC ₅₀高达 69 nM）、抗雄激素抗性和可能是 AR 结合功能的非传统靶向位点 3。其中，4c在 LNCaP 异种移植研究中在口服给药后表现出有效的肿瘤生长抑制作用。这项工作为 AR 拮抗剂提供了一种新的化学支架，并为 PCa 治疗的发展提供了新的视角。