Novel, non-steroidal, selective androgen receptor modulators (SARMs) with anabolic activity in bone and muscle and improved safety profile.
Novel, non-steroidal, selective androgen receptor modulators (SARMs) with anabolic activity in bone and muscle and improved safety profile.
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DOI：
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发表时间：
2002-03
影响因子：
1.9
通讯作者：
J. Rosen;A. Negro-Vilar
中科院分区：
文献类型：
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作者：
J. Rosen;A. Negro-Vilar
一种治疗男性骨质疏松症的新方法是开发选择性雄激素受体调节剂（SARM），其可以刺激新骨的形成，同时显著降低前列腺中的增殖活性，以及降低女性中的男性化活性。在过去的几年里，我们制定了一项计划来发现和开发新型、非甾体、口服活性选择性雄激素受体调节剂（SARM），以提供更好的治疗益处并降低风险和副作用。在最近的研究中，我们使用了一只睾丸成熟的睾丸切除（ORX）雄性大鼠作为雄性性腺功能减退症的动物模型，用于评估LGD 2226（一种非甾体、非芳香化和非5 α还原性SARM）的疗效。我们评估了LGD 2226对骨转换、骨量和骨强度的活性，还评估了对经典雄激素依赖性靶点（如前列腺、精囊和肌肉）的影响。在ORX动物中观察到骨密度的大量损失，并且SARM以及标准雄激素防止了这种损失。骨转换的生化标志物显示，在雄激素缺乏大鼠中骨吸收早期增加，在4个月的给药期间，经口给予SARM（LGD 2226）的ORX动物中骨吸收受到抑制。通过组织形态学和力学分析检测到结构特性和骨强度的差异，证明了LGD 2226对雄激素缺乏大鼠骨质量的有益作用。皮质骨的组织形态计量学分析显示，LGD 2226在骨膜骨中具有明显的合成代谢活性。LGD 2226能够通过刺激骨形成，同时抑制骨转换，预防ORX大鼠的骨丢失并维持骨质量。LGD 2226还对肛提肌产生合成代谢活性。总之，这些结果表明，口服活性，非甾体SARMs可能是有用的治疗肌肉和骨骼在老年性腺功能减退的男性通过他们的合成代谢活动。由于SARM既防止骨丢失，又刺激新骨的形成，因此相对于目前使用的抗吸收疗法，它们可能具有显著的优势。再加上它们在肌肉中的活性和维持或恢复性欲的能力，它们为男性和女性激素替代提供了新的治疗方法。
A novel approach to the treatment of osteoporosis in men, and possibly women, is the development of selective androgen receptor modulators (SARMs) that can stimulate formation of new bone with substantially diminished proliferative activity in the prostate, as well as reduced virilizing activity in women. Over the last several years, we have developed a program to discover and develop novel, non-steroidal, orally-active selective androgen receptor modulators (SARMs) that provide improved therapeutic benefits and reduce risk and side effects. In recent studies, we have used a skeletally mature orchiectomized (ORX) male rat as an animal model of male hypogonadism for assessing the efficacy of LGD2226, a nonsteroidal, non-aromatizable, and non-5alpha-reducible SARM. We assessed the activity of LGD2226 on bone turnover, bone mass and bone strength, and also evaluated the effects exerted on classic androgen-dependent targets, such as prostate, seminal vesicles and muscle. A substantial loss of bone density was observed in ORX animals, and this loss was prevented by SARMs, as well as standard androgens. Biochemical markers of bone turnover revealed an early increase of bone resorption in androgen-deficient rats that was repressed in ORX animals treated with the oral SARM, LGD2226, during a 4-month treatment period. Differences in architectural properties and bone strength were detected by histomorphometric and mechanical analyses, demonstrating beneficial effects of LGD2226 on bone quality in androgen-deficient rats. Histomorphometric analysis of cortical bone revealed distinct anabolic activity of LGD2226 in periosteal bone. LGD2226 was able to prevent bone loss and maintain bone quality in ORX rats by stimulating bone formation, while also inhibiting bone turnover. LGD2226 also exerted anabolic activity on the levator ani muscle. Taken together, these results suggest that orally-active, non-steroidal SARMs may be useful therapeutics for both muscle and bone in elderly hypogonadal men through their anabolic activities. Since SARMs both prevent bone loss, and also stimulate formation of new bone, they may have significant advantages relative to currently used anti-resorptive therapies. Coupled with their activity in muscle and their ability to maintain or restore libido, they offer new therapeutic approaches for male and female hormone replacement.