Development of ER beta agonists to treat post-menopausal memory decline

 描述（由申请人提供）：绝经后妇女雌激素水平下降已被证明会增加记忆丧失和阿尔茨海默病的风险。虽然这些影响可能会使用激素替代疗法来减轻，但传统的基于雌激素的激素疗法也会导致癌症，心脏病和中风的风险增加。这些不良反应主要由雌激素受体α（ERα）介导。与更年期相关，衰老显著降低海马中ERα和ERβ的水平，表明与年龄相关的记忆力下降有关;但ERβ仍然是主要的同种型。我们推测，绝经后妇女年龄相关性记忆减退的最佳治疗可能是通过选择性激活海马ERβ的治疗，从而避免ERβ激动剂的不良反应。但是，目前的ERβ激动剂对β与α亚型只有适度的选择性，因此存在一些癌症风险。因此，需要更有效和选择性的ERβ激动剂，作为绝经后年龄相关记忆衰退的潜在治疗方法。本项目的目的是开发和表征一类新的高选择性ERβ激动剂，用于治疗绝经后年龄相关的记忆衰退。这包括基于我们最近报道的新型化合物的ERβ类似物的计算设计、合成、体外测试和体内功效测量。我们将使用这类新的化合物来验证我们的假设，即选择性ERβ激动剂是治疗绝经后记忆衰退的有效治疗干预措施，其不良反应（包括癌症）的可能性极小。我们的目标是：1.环庚烷-羟甲烷类ERβ激动剂的设计、合成及体外活性测试。使用对接、生物电子等排体和基于配体的方法对我们的先导化合物进行计算优化，然后合成和测试预测具有最高亲和力和选择性的化合物。 2.优化环庚烷-羟基甲烷ERβ激动剂的体外ADME性质。检测CYP 450代谢和抑制（CYP 3A 5、CYP 2D 6、CYP 2C 8/9、CYP 1A 2）以及hERG结合和肠道转运，使用Caco试验建模。合成和测试类似物以优化体外ADME特性，同时保持对ERβ的高亲和力和选择性。 3.在适当的小鼠模型中确定ERβ激动剂对认知增强的功效。在卵巢切除小鼠中，使用新的物体识别测定法确定前3种化合物对海马记忆巩固的影响。还将评估对基于雌激素的ERK/MAPK级联激活的影响。

 DESCRIPTION (provided by applicant): Estrogen level decreases in post-menopausal women have been shown to increase the risk of memory loss and Alzheimer's disease. While these effects might be mitigated using hormone replacement therapy, traditional estrogen-based hormone therapies also lead to increased risk of cancer, heart disease and stroke. These adverse effects are mediated predominantly by estrogen receptor-alpha (ERα). Relevant to menopause, aging significantly reduces levels of ERα and ERβ in the hippocampus, suggesting an association with age-related memory decline; but, ERβ remains the predominant isoform. We hypothesize that an optimal treatment for age-related memory decline in post-menopausal women may be via treatment that selectively activates hippocampal ERβ, thereby avoiding the adverse effects of ERβ agonists. But, current ERβ agonists have only modest selectivity for the beta versus alpha isoform, so present some cancer risk. Therefore, there is a need for more potent and selective ERβ agonists, as potential treatments for postmenopausal age-related memory decline. The objective of this project is to develop and characterize a new class of highly selective ERβ agonists, to treat postmenopausal age-related memory decline. This includes computational design, synthesis, in vitro testing, and in vivo efficacy measurements of ERβ analogs based on a novel compound we have recently reported. We will use this new class of compounds to test our hypothesis that selective ERβ agonists are an effective therapeutic intervention for treatment of postmenopausal memory decline, with minimal potential for adverse effects - including cancer. Our Aims Are to: 1. Design, synthesize and test cycloheptane-hydroxymethane ERβ agonists in vitro. Perform computational optimization of our lead compound using docking, bioisostere and ligand-based methods, followed by synthesis and testing of compounds predicted to bind with highest affinity and selectivity. 2. Optimize in vitro ADME properties of the cycloheptane-hydroxymethane ERβ agonists. Test for CYP450 metabolism and inhibition (CYP3A5, CYP2D6, CYP2C8/9, CYP1A2), as well as hERG binding and intestinal transport, modeled using a Caco assay. Synthesize and test analogs to optimize for improved in vitro ADME properties, while retaining high affinity and selectivity for ERβ. 3. Determine efficacy of ERβ agonists for cognitive enhancement in an appropriate mouse model. In ovariectomized mice, determine effect of the top 3 compounds on hippocampal memory consolidation using a novel object recognition assay. Effect on the estrogen-based activation of the ERK/MAPK cascade will also be assessed.