Janssen Research and Development LLC, Welsh&McKean Roads, Spring House, PA 19477, USA.
J Steroid Biochem Mol Biol. 2013 Mar;134:51-8. doi: 10.1016/j.jsbmb.2012.10.015. Epub 2012 Oct 23.
Selective androgen receptor modulators (SARMs) are androgens with tissue-selective activity. SARMs that have anabolic activity on muscle while having minimal stimulatory activity on prostate are classified as SARM agonists. They can be used to prevent the loss of lean body mass that is associated with cancer, immunodeficiency, renal disease and aging. They may also have anabolic activity on bone; thus, unlike estrogens, they may reverse the loss of bone strength associated with aging or hypogonadism. Our in-house effort on SARM program discovers a nonsteroidal androgen receptor ligand with a unique imidazolopyrazole moiety in its structure. In vitro, this compound is a weak androgen receptor binder and a weak androgen agonist. Despite this, in orchidectomized mature rats it is an effective SARM agonist, with an ED(50) on levator ani muscle of 3.3mg/kg and an ED(50) on ventral prostate of >30mg/kg. It has its maximal effect on muscle at the dose of 10mg/kg. In addition, this compound has mixed agonistic and antagonistic activities on prostate, reducing the weight of that tissue in intact rats by 22% at 10mg/kg. The compound does not have significant effect on gonadotropin levels or testosterone levels in both orchidectomized and intact male rats. It does not have notable progestin, estrogen or glucocorticoid agonistic or antagonistic activity in rats. In a female sexual behavior model, it improves the sexual desire of ovariectomized female rats for sexually mature intact males over nonsexually ovariectomized females. Overall, the imidazolopyrazole is a potent prostate-sparing candidate for development as a SARM agonist with an appropriate pharmacological profile for clinical benefit in muscle-wasting conditions and female sexual function disorders.
选择性雄激素受体调节剂 (SARM) 是具有组织选择性活性的雄激素。对肌肉具有合成代谢活性而对前列腺刺激最小的 SARM 被归类为 SARM 激动剂。它们可用于预防与癌症、免疫缺陷、肾脏疾病和衰老相关的瘦肉量损失。它们也可能对骨骼具有合成代谢活性；因此，与雌激素不同，它们可能逆转与衰老或性腺功能减退相关的骨强度损失。我们在 SARM 项目上的内部努力发现了一种非甾体雄激素受体配体，其结构中具有独特的咪唑并吡唑部分。在体外，该化合物是一种弱雄激素受体结合物和弱雄激素激动剂。尽管如此，在去势成熟大鼠中，它是一种有效的 SARM 激动剂，其对提肛肌的 ED50 为 3.3mg/kg，对前列腺腹侧的 ED50 大于 30mg/kg。在 10mg/kg 的剂量下，它对肌肉的效果最大。此外，该化合物对前列腺具有混合激动和拮抗作用，在 10mg/kg 时使完整大鼠的前列腺组织重量减少 22%。该化合物对去势和完整雄性大鼠的促性腺激素水平或睾酮水平均无显著影响。它在大鼠中对孕激素、雌激素或糖皮质激素没有明显的激动或拮抗作用。在女性性行为模型中，它改善了去势雌性大鼠对性成熟完整雄性的性欲，超过了非性去势雌性。总的来说，咪唑并吡唑是一种有效的前列腺保护候选物，可作为 SARM 激动剂开发，具有适当的药理学特征，可在肌肉减少症和女性性功能障碍等情况下带来临床益处。
