Dimethandrolone undecanoate: A new potent orally active androgen with progestational activity
Dimethandrolone undecanoate: A new potent orally active androgen with progestational activity
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DOI：
10.1210/en.2005-1524
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发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Reel, Jerry R.
中科院分区：
文献类型：
--
作者：
Attardi, Barbara J.;Hild, Sheri A.;Reel, Jerry R.
甲美雄龙（DMA）是甲美雄龙（DMAU; 7 α， 11 β -二甲基-19-去甲睾酮）的17 β -十一烷酸酯，是一种有效的雄激素，目前正在开发用于男性治疗。裂解17 -酯键释放具有生物活性的DMA。本研究对DMAU和DMA在体内和体外的活性进行了研究。在去势大鼠的生物测定中，口服DMAU是有活性的，当给药sc时，单剂量产生延长的雄激素活性和抑制黄体生成素，同时持续循环水平的DMA。在人雄激素受体表达载体和具有三种激素反应元件的荧光素酶报告质粒共转染的CV-1细胞中，DMA、其他19-去甲雄激素和C-19雄激素以高亲和力结合重组大鼠雄激素受体，在刺激荧光素酶活性(EC50, 10(-10)-10（M)(-9)）方面具有同等效力。由于已知多种19-去雄激素也可与孕激素受体（PR）结合并在体内具有孕活性，因此我们评估了DMA与兔PR和重组人PR- a和PR- b的结合亲和力，以及其在T47DCO人乳腺癌细胞中诱导PR介导的转录和内源性碱性磷酸酶活性的能力。在T47DCO细胞中，10(M)(-8) DMA和其他19-去甲雄激素对黄体酮/糖皮质激素/雄激素反应元件胸苷激酶-荧光素酶报告质粒的转录刺激程度与R5020相同，R5020是强效黄体酮progestone (EC50，与10（M)（-9）相似）。但C-19雄激素没有效果。抗孕激素对DMA和其他19-去雄激素诱导的T47DCO细胞的转激活和碱性磷酸酶活性有较强的抑制作用，而抗雄激素对T47DCO细胞有较弱的抑制作用。通过诱导子宫内膜腺移植来评估，在雌激素刺激的未成熟雌性兔中，DMA和DMAU也表现出剂量依赖性的孕活性。DMA的双雄激素和孕激素活性使其成为单剂男性避孕药和男性雄激素治疗的潜在候选者，目前正在进行的药代动力学和毒性研究取得成功的结果。
Dimethandrolone (DMA), the 17 beta-undecanoic acid ester of dimethandrolone (DMAU; 7 alpha, 11 beta-dimethyl-19-nortestosterone) is a potent androgen currently in development for therapeutic uses in men. Cleavage of the 17 beta-ester bond liberates the biologically active DMA. In this study we investigated the activity of DMAU and DMA both in vivo and in vitro. DMAU was active orally in castrate rat bioassays, and when administered sc, a single dose produced prolonged androgenic activity and suppression of LH with sustained circulating levels of DMA. DMA, other 19-norandrogens, and C-19 androgens bound to recombinant rat androgen receptor with high affinity and were equipotent in stimulating luciferase activity (EC50, 10(-10)-10(M)(-9)) in CV-1 cells cotransfected with a human androgen receptor expression vector and a luciferase reporter plasmid with three hormone response elements. Because various 19-norandrogens are also known to bind to progestin receptors (PR) and to possess progestational activity in vivo, we evaluated the binding affinity of DMA for rabbit PR and recombinant human PR-A and PR-B and its ability to induce PR-mediated transcription and endogenous alkaline phosphatase activity in T47DCO human breast cancer cells. DMA and related 19-norandrogens bound with high affinity to both rabbit and human PR, whereas the less active 11 alpha-methyl stereoisomer of DMA and C-19 androgens showed low or negligible binding to PR. In T47DCO cells, 10(M)(-8) DMA and other 19-norandrogens stimulated transcription of a progestin/glucocorticoid/ androgen response element-thymidine kinase-luciferase reporter plasmid to the same extent as R5020, the potent progestin promegestone (EC50, similar to 10(M)(-9)), but C-19 androgens had no effect. Antiprogestins were potent inhibitors of transactivation and alkaline phosphatase activity induced by DMA and other 19-norandrogens in T47DCO cells, whereas antiandrogens were weak inhibitors. DMA and DMAU also exhibited dose-dependent progestational activity in the estrogen-primed immature female rabbit, as assessed by induction of endometrial gland arborization. The dual androgenic and progestational activities of DMA make it a potential candidate for a single-agent male contraceptive as well as for androgen therapy in men, pending a successful outcome of pharmacokinetic and toxicity studies currently in progress.