Estrogen receptor reprogramming ligands for the prevention of protracted menopausal symptoms and chronic diseases

项目概要/摘要 由于寿命延长，影响更年期妇女的健康问题变得越来越普遍。 潮热、睡眠问题和情绪波动是典型的短期症状，可能会产生负面影响 对生活质量和工作效率的影响。慢性疾病如骨质疏松症的发病率增加， 肥胖、糖尿病、代谢综合征和心血管疾病与长期雌激素不足有关 绝经后。月经激素治疗（MHT）可有效减轻更年期症状， 预防一些慢性疾病，但根据妇女健康倡议（WHI），长期治疗 风险大于收益。绝经期妇女中使用MHT的人数自发表以来急剧下降 WHI的数据。目前推荐MHT用于潮热和阴道炎的5年短期治疗 症状MHT不再被推荐用于慢性病的一级预防。无数 更年期妇女继续焦急地等待更安全的长期MHT来改善她们的生活质量， 健康与此同时，许多女性选择未经证实的补充剂来缓解更年期症状。那里 是开发可用于长期治疗的新MHT制剂的显著未满足的需求 因为许多妇女遭受更年期症状超过五年，慢性疾病增加， 整个更年期。在MHT被批准近80年后，仍然没有长期安全的MHT配方- 长期治疗我们的目标是开发一种更安全的MHT配方，可以长期用于治疗长期 更年期症状和预防慢性疾病，如骨质疏松症，糖尿病，肥胖，代谢 综合征我们发现了一类我们称之为雌激素受体（ER）重编程配体的化合物。 我们发现，当重编程配体与雌二醇（E2）结合时，一组新的基因受到调节， 不受重编程配体或E2单独调控的基因。重编程配体阻断了 人乳腺癌细胞的增殖和小鼠子宫响应E2的生长。我们的目标是 通过将MHT的E2蛋白组分替换为E2/重编程配体组合， 重新编程配体并将其加入到单独的雌激素制剂中。我们的假设是 E2/重编程配体组合将比单一雌激素和雌激素/MHT更安全 目前市场上的制剂，以便它们可以用作长期治疗，以防止长期的 更年期症状和慢性疾病。我们最初的重编程配体是天然化合物。到 为了提高其药理活性和加强其专利保护，我们制备并鉴定了几种 在基于细胞的测定中表现类似于天然重编程配体的合成类似物。作为下一个 在临床开发途径的第一步，我们将在动物模型中测试合成类似物，以选择领先的 类似物，这是最有效和安全的未来临床试验。

Project Summary/Abstract Because of longer lifespans, health problems affecting menopausal women are becoming increasingly common. Hot flashes, sleep issues, and mood swings are typical short-term symptoms that can have a negative impact on quality of life and productivity at work. An increased incidence of chronic disorders such as osteoporosis, obesity, diabetes, metabolic syndrome, and cardiovascular disease is linked to long-term estrogen insufficiency following menopause. Menopausal hormone therapy (MHT) is effective at reducing menopausal symptoms and preventing some chronic diseases, but according to the Women's Health Initiative (WHI), long-term therapy has more risks than benefits. The use of MHT among menopausal women has sharply dropped since the publication of the WHI data. MHT is currently recommended for a 5-year short-term treatment of hot flashes and vaginal symptoms. MHT is no longer recommended for the primary prevention of chronic diseases. Countless menopausal women continue to wait anxiously for a safer long-term MHT to improve their quality of life and health. In the meantime, many women opt for unproven supplements to relieve menopausal symptoms. There is a significant unmet need for developing new MHT formulations that can be utilized for long-term therapy because many women suffer from menopausal symptoms for more than five years and chronic diseases increase throughout menopause. Almost 80 years after MHT was approved, there is still no MHT formula safe for long- term therapy. Our objective is to develop a safer MHT formula that can be used long-term to treat protracted menopausal symptoms and prevent chronic diseases, such as osteoporosis, diabetes, obesity, and metabolic syndrome. We discovered a class of compounds that we termed estrogen receptor (ER) reprogramming ligands. We found that when a reprogramming ligand is combined with estradiol (E2), a new set of genes are regulated that are not regulated by the reprogramming ligand or E2 alone. The reprogramming ligand blocked the proliferation of human breast cancer cells and the growth of the mouse uterus in response to E2. Our goal is to create an E2/reprogramming ligand combination by replacing the progestin component of MHT with a reprogramming ligand and adding it to the estrogen-alone formulation. Our hypothesis is that the E2/reprogramming ligand combination will be safer than the single estrogen and estrogen/progestin MHT preparations currently on the market so that they can be used as a long-term therapy to prevent protracted menopausal symptoms and chronic diseases. Our original reprogramming ligand was a natural compound. To improve its pharmacological properties and strengthen its patent protection, we prepared and identified several synthetic analogs that behave similarly to the natural reprogramming ligand in cell-based assays. As the next step in the clinical development pathway, we will test the synthetic analogs in animal models to select the lead analog that is the most effective and safe for future clinical trials.