Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5442-5. doi: 10.1016/j.bmcl.2011.06.122. Epub 2011 Jul 2.
Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.
我们研究了化学起始点，以期下调雄激素受体，以此作为治疗晚期前列腺癌的一种方法。尽管用于肌肉内给药的典型甾体类下调剂，如 6a，显示出细胞效力不足，但源于新型雄激素受体配体 8a 的药物化学方案导致了 6-[4-(4-氰基苄基)哌嗪-1-基]-3-(三氟甲基)[1,2,4]三唑并[4,3-b]哒嗪（10b），在临床前模型中经口服给药后，其血浆水平较高，弥补了中等的细胞效力。
