Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridino[5,6-g]quinolines
Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridino[5,6-g]quinolines
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DOI：
10.1021/jm970699s
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发表时间：
1998-02-12
影响因子：
7.3
通讯作者：
Jones, TK
中科院分区：
文献类型：
--
作者：
Hamann, LG;Higuchi, RI;Jones, TK
通过与人雄激素受体(HAR)的细胞共转染实验，发现了一种新的非甾体类抗雄激素药效团。这一系列AR拮抗剂的结构特征是一个线性的三环1，2-二氢吡啶并[5，6-g]喹啉核心。类似物抑制AR介导的报告基因的表达，并与AR结合，与任何已知的AR拮抗剂一样有效或更好。几个类似物在AR拮抗的经典啮齿动物模型中也显示出出色的体内活性，抑制大鼠腹侧前列腺和精囊的生长，而不会像其他AR拮抗剂那样伴随血清促性腺激素和睾酮水平的升高。围绕这种药效团的结构-活性关系的研究导致了对AR具有完全特异性的分子，对前列腺癌患者常见的AR突变体具有拮抗活性，并提高了体内疗效。基于这一系列化合物的分子有可能为前列腺癌和其他雄激素依赖型疾病的治疗提供独特和有效的临床机会。
A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.