Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: Potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats
Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: Potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats
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DOI：
10.1210/en.2006-0843
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发表时间：
2007-01-01
期刊：
影响因子：
4.8
通讯作者：
Hamann, Lawrence G.
中科院分区：
文献类型：
--
作者：
Ostrowski, Jacek;Kuhns, Joyce E.;Hamann, Lawrence G.
一种新型、高效、口服活性、非甾体组织选择性雄激素受体 (AR) 调节剂 (BMS-564929) 已被鉴定出来，并且该化合物已进入临床试验阶段，用于治疗与年龄相关的功能衰退。 BMS-564929 是一种体外亚纳摩尔 AR 激动剂，与其他类固醇激素受体相比，对 AR 具有高度选择性，并且与 SHBG 或芳香酶没有显着的相互作用。在去势雄性大鼠中进行的剂量反应研究表明，BMS-564929 在刺激提肛肌生长方面比睾酮 (T) 更有效，并且与 T 不同的是，BMS-564929 对肌肉和前列腺具有高度选择性。通过 X 射线晶体学揭示了 BMS-564929 与 AR 相对于天然激素的结合相互作用的关键差异，包括位于配体结合结构域的特定螺旋中的几个独特接触，这对于共调节蛋白的募集很重要。其他药理学研究的结果有效地排除了这种独特的口服活性雄激素所观察到的组织选择性的替代机制贡献。由于对前列腺的潜在过度刺激作用和不方便的给药途径的担忧是限制 T 临床使用的主要缺点，因此 BMS-564929 所表现出的有效口服活性和组织选择性有望产生临床特征，为 T 在肌肉和其他组织中所证明的有益作用提供更有利的安全窗口。
A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor ( AR) modulator ( BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone ( T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.