Selective androgen receptor modulators as function promoting therapies
Selective androgen receptor modulators as function promoting therapies
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DOI：
10.1097/mco.0b013e32832a3d79
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发表时间：
2009-05-01
影响因子：
3.1
通讯作者：
Jasuja, Ravi
中科院分区：
文献类型：
--
作者：
Bhasin, Shalender;Jasuja, Ravi
在过去的十年中，选择性雄激素受体调节剂（SARMs）的研究取得了前所未有的进展，这些调节剂可以改善身体功能和骨骼健康，同时又不会对前列腺和心血管疾病产生不利影响。本文综述了SARM的历史演变，SARM发展的基本原理，以及睾酮作用和SARM选择性的机制。最近的发现尽管甾体类sarm早在20世纪40年代就已经存在，但一些非甾体类sarm不作为CYP19芳香化酶或5 α -还原酶的底物，在肌肉和骨骼中作为完全激动剂，在前列腺中作为部分激动剂，仍在开发中。甾体和非甾体化合物与雄激素受体（AR）的不同相互作用决定了它们独特的药理作用。配体结合诱导配体结合域发生特异性构象变化，从而调节AR与共调节因子之间的表面拓扑结构和蛋白-蛋白相互作用，从而实现组织特异性基因调控。临床前研究已经证明SARMs能够在不同程度的前列腺保留的临床前啮齿动物模型中增加肌肉和骨量。SARMs在人体中的一期试验报告了无脂肪质量有适度的增加。ysarms有望成为一类新的功能促进合成代谢疗法，用于许多临床适应症，包括与衰老和慢性疾病、虚弱、癌症恶病质和骨质疏松症相关的功能限制。
Purpose of reviewThe past decade has witnessed an unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity.Recent findingsAlthough steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5 alpha-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with androgen receptor (AR) contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand-binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass.SummarySARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis.