Development of EGX358, an ER-beta Agonist to Treat Hot Flashes & Menopause-Related Memory Loss

美国有6000万50岁以上的女性，其中超过一半的人出现了阴性症状 更年期。我们的市场研究表明，女性渴望的更年期主要症状 治疗方法是潮热和记忆障碍。而至少70%的女性在 在更年期过渡期，有效的治疗方法很少。雌激素治疗(ET)已成为主要的治疗方法。 治疗更年期症状，到2022年，激素治疗市场预计将达到280亿美元。 然而，ET与癌症和心脏病的风险增加有关，导致许多女性放弃 治疗或使用无效或未经证实的替代治疗。不仅是缺乏安全和有效的 治疗会扰乱女性的生活，但更年期症状得不到治疗的女性会遭受更大的伤害 与使用ET或ARE的女性相比，医疗成本、看医生的次数更多，工作效率更低 没有任何症状。ET负效应的主要罪魁祸首是雌激素受体α(ERα)，它是两种激素之一 雌激素影响细胞功能的细胞内内质网。而ERα的激活与 ET导致的健康风险，ERβ的激活有利于血管运动功能和认知。因此，选择性地激活 ERβ可能会减少更年期症状，而不会出现有害健康后果的风险。埃斯特里格尼克斯的 使命是开发药物，帮助女性活得更健康、更长寿。这项提案的总体目标是 就是优化和开发我们的先导化合物，新型ERβ激动剂egx358，作为治疗烫伤的药物 更年期女性的闪光和记忆力下降。这项研究具有创新性，因为EGX358是 选择性ERβ激动剂迄今已有报道，它是一种独特的结构类别，具有基于环己烷的 饱和环系，由羟亚甲基取代。我们的中心假设是，EGX358将 缓解更年期症状，包括潮热和记忆力下降，在一种中年小鼠模型中 更年期，适合于基于初步药代动力学和过程的进一步临床前研究 化学反应。这一假设是基于我们使用年轻的去卵巢小鼠更年期模型进行的研究 显示急性和/或慢性口服EGX358治疗减轻药物引起的潮热并增强 记忆形成，不影响乳腺癌细胞增殖，也不会对核造成非靶点效应 激素受体结合或组织病理学。我们的假设将在三个具体目标中进行检验，旨在： 1)证明EGX358能减少潮热和增强记忆。 更年期，2)表现出极低的毒性和良好的药代动力学(PK)稳定性 优化模拟)，3)开发适合于方法转移到 CGMP实验室为临床试验生产足够的材料。这项第二阶段的启用工作将证明 EGX358在更年期小鼠模型中改善记忆和减少潮热，具有可接受的PK-PD (药动学-动力学)性质，是安全的，可以合成足够数量的临床研究。

There are >60 million women over age 50 in the U.S., of which more than half experience negative symptoms of menopause. Our market research indicates that major symptoms of menopause for which women desire treatment are hot flashes and memory dysfunction. While at least 70% of women suffer these symptoms during the menopausal transition, few effective treatments are available. Estrogen therapy (ET) has been the primary treatment for menopausal symptoms, with the hormone therapy market expected to reach $28 billion by 2022. However, ET is associated with increased risks of cancer and heart disease, leading many women to forgo treatment or to use ineffective or unproven alternative treatments. Not only is the lack of safe and effective treatments disruptive to women’s lives, but women whose menopausal symptoms go untreated incur greater healthcare costs, more physician visits, and lower work productivity than women who use ET or are asymptomatic. The primary culprit in the negative effects of ET is estrogen receptor alpha (ERα), one of two intracellular ERs through which estrogens affect cellular function. Whereas activation of ERα is associated with ET-induced health risks, ERβ activation benefits vasomotor function and cognition. Thus, selective activation of ERβ may reduce menopausal symptoms without incident risk of detrimental health outcomes. Estrigenix’s mission is to develop drugs to help women live healthier and longer lives. The overall objective of this proposal is to optimize and develop our lead compound, the novel ERβ agonist EGX358, as a therapeutic to treat hot flashes and memory decline in menopausal women. This research is innovative because EGX358 is the most selective ERβ agonist reported to date, and is in a unique structural class possessing a cyclohexane-based saturated ring system, substituted with a hydroxymethylene group. Our central hypothesis is that EGX358 will alleviate symptoms of menopause, including hot flashes and memory decline, in a middle-aged mouse model of menopause, and is suitable for further preclinical studies based on preliminary pharmacokinetics and process chemistry. This hypothesis is based on our studies using a young ovariectomized mouse model of menopause showing that acute and/or chronic oral EGX358 treatment alleviates drug-induced hot flashes and enhances memory formation, without affecting breast cancer cell proliferation or causing off-target effects on nuclear hormone receptor binding or tissue pathology. Our hypothesis will be tested in three specific aims designed to: 1) demonstrate that EGX358 can reduce hot flashes and enhance memory in a middle-aged mouse model of menopause, 2) demonstrate minimal toxicity and favorable pharmacokinetic (PK) stability for EGX358 (or an optimized analog), 3) develop process chemistry scaleup synthesis of EGX358 suitable for method transfer to a cGMP lab to produce sufficient material for clinical trials. This Phase II enabling work will demonstrate that EGX358 improves memory and reduces hot flashes in a mouse model of menopause, has acceptable PK-PD (pharmacokinetic-dynamic) properties, is safe, and can be synthesized in sufficient quantities for clinical studies.