Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.
Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.
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DOI：
10.1021/jm061329j
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发表时间：
2007-04
影响因子：
7.3
通讯作者：
R. Higuchi;K. L. Arienti;Francisco J. López;N. S. Mani;D. Mais;T. Caferro;Y. Long;T. K. Jones
中科院分区：
文献类型：
--
作者：
R. Higuchi;K. L. Arienti;Francisco J. López;N. S. Mani;D. Mais;T. Caferro;Y. Long;T. K. Jones
最近对口服雄激素的兴趣推动了对用于激素替代疗法和作为合成代谢剂的新雄激素的研究。在追求这一点，我们已经发现了一系列新的雄激素受体调节剂衍生自7 H-[1，4]恶嗪并[3，2-g]喹啉-7-酮。这些化合物的合成和竞争性结合试验和雄激素受体转录激活试验进行了评价。该系列的许多化合物在体外表现出个位数纳摩尔激动剂活性。此外，先导化合物（R）-16 e在测量这些药剂的雄激素和合成代谢性质的已建立啮齿动物模型中具有口服活性。在该测定中，（R）-16 e在肌肉中显示出完全功效，并且在100 mg/kg下仅部分刺激前列腺。这些数据表明，这些化合物可用作选择性雄激素受体调节剂或SARM。该系列代表了用于雄激素替代疗法的一类新化合物。
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.