Maximov Philipp Y, Lee Theresa M, Jordan V Craig
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Curr Clin Pharmacol. 2013 May;8(2):135-55. doi: 10.2174/1574884711308020006.
Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists or antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with postmenopausal women's health, including hormone responsive cancer and osteoporosis. Tamoxifen, a failed contraceptive is currently used to treat all stages of breast cancer, chemoprevention in women at high risk for breast cancer and also has beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene, a failed breast cancer drug, is the only SERM approved internationally for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they also have some potentially serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis or prevent and treat breast cancer. The search for the 'ideal' SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potentially greater efficacy and potency than previous SERMs, have been investigated for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are available or are awaited for each SERM so that a true understanding of the therapeutic potential of these compounds can be obtained. In this article, we describe the discovery and development of the group of medicines called SERMs. The newer SERMs in late development: ospemifene, lasofoxifene, bazedoxifene, are arzoxifene are described in detail.
选择性雌激素受体调节剂（SERM）是结构各异的化合物，它们在靶器官中作为雌激素受体激动剂或拮抗剂与细胞内雌激素受体相互作用。在过去十年中，对这些药物进行了深入研究，已证明它们是用于治疗与绝经后女性健康相关的不同病症的高度通用的一类药物，包括激素反应性癌症和骨质疏松症。他莫昔芬，一种失败的避孕药，目前用于治疗乳腺癌的各个阶段，对乳腺癌高危女性进行化学预防，并且对绝经后女性的骨矿物质密度和血脂也有有益影响。雷洛昔芬，一种失败的乳腺癌药物，是国际上唯一获批用于预防和治疗绝经后骨质疏松症及椎体骨折的SERM。然而，尽管这些SERM有许多益处，但它们也有一些潜在的严重不良反应，如血栓栓塞性疾病，就他莫昔芬而言，还会引发子宫癌。鉴于预防骨质疏松症或预防和治疗乳腺癌需要长期治疗，这些不良反应成为一个主要问题。目前正在寻找“理想”的SERM，它对骨骼和血脂具有雌激素样作用，对子宫具有中性作用，对乳腺组织具有抗雌激素作用，且没有当前疗法相关的不良反应。奥昔芬、拉索昔芬、巴多昔芬和阿佐昔芬是新型SERM分子，其效力和效能可能比先前的SERM更大，已对它们用于治疗和预防骨质疏松症进行了研究。在动物模型中，已证明这些药物与传统激素替代疗法具有相当的疗效，且可能具有安全性改善的迹象。每种SERM正在进行的III期试验的临床疗效数据已经可得或有待获取，以便能够真正了解这些化合物的治疗潜力。在本文中，我们描述了被称为SERM的这一类药物的发现和研发过程。详细介绍了处于后期研发阶段的新型SERM：奥昔芬、拉索昔芬、巴多昔芬和阿佐昔芬。
