Chugai Pharmaceutical Co., Ltd, Gotemba, Shizuoka, Japan.
Bioorg Med Chem. 2010 Dec 1;18(23):8150-7. doi: 10.1016/j.bmc.2010.10.023. Epub 2010 Oct 15.
A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.
我们合成了一系列 5,5-二甲基硫代海因衍生物，并对其进行了雄激素受体纯拮抗活性评估，以期将其用于治疗去势抵抗性前列腺癌。由于我们之前报道的 CH4933468 存在激动剂代谢物的问题，因此我们应用了两种策略来鉴定新型硫代海因衍生物。一种策略是用苯磺酰胺取代烷基亚磺酰胺，以避免产生激动剂代谢物。另一种策略是用吡啶环取代苯环，以提高体内效力并降低 hERG 亲和力。药理测定表明，CH5137291（17b）是一种强效的雄激素受体纯拮抗剂，不会产生激动剂代谢物。此外，CH5137291 完全抑制了去势抵抗性前列腺癌模型 LNCaP-BC2 的体内肿瘤生长。
