Abstract：
Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes. We assessed the impact of structural modifications to the parent compound OSU-ERβ-12 on receptor subtype binding selectivity using cell-free binding assays. Functional selectivity was evaluated by transactivation in HEK-293 cells overexpressing human or murine estrogen receptors. In vivo selectivity was examined through the uterotrophic effects of the analogs after oral administration in estrogen-naïve female mice. Furthermore, we evaluated the in vivo pharmacokinetics of the analogs following single dose IV and oral administration. Regarding selectivity, a single compound exhibited greater functional selectivity than OSU-ERβ-12 for human ERβ. However, like others in the meta-carborane series, its poor in vivo pharmacokinetics limit its suitability for further development. Surprisingly, and at odds with their pharmacokinetic and in vitro human activity data, most analogs potently induced uterotrophic effects in estrogen-naïve female mice. Further investigation of activity in HEK293 cells expressing murine estrogen receptors revealed species-specific differences in the ER-subtype selectivity of these analogs. Our findings highlight species-specific receptor pharmacology and the challenges it poses to characterizing developmental therapeutics in preclinical species. Significance Statement This study investigates para- and meta-substituted carborane analogs targeting estrogen receptors, revealing the greater selectivity of carborane analogs for human ERβ compared to the mouse homolog. These findings shed light on the intricacies of using preclinical species in drug development to predict human pharmacology. The report also provides insights for the refinement and optimization of carborane analogs as potential therapeutic agents for estrogen-related disease states.
摘要：
雌激素受体是治疗激素紊乱和雌激素依赖性恶性肿瘤的重要药理学靶点。假设雌激素受体（ER）β的选择性激活可提供治疗益处，并降低与ERα活性相关的有害雌激素副作用的风险。然而,由于受体亚型之间的高度序列和结构同源性，激活ERβ而不激活α具有挑战性。我们使用无细胞结合测定评估了对母体化合物OSU-ERβ-12的结构修饰对受体亚型结合选择性的影响。通过在过表达人或鼠雌激素受体的HEK-293细胞中的反式激活来评估功能选择性。通过在未雌激素的雌性小鼠中口服施用后类似物的子宫营养作用来检查体内选择性。此外，我们评估了单剂量IV和口服给药后类似物的体内药代动力学。关于选择性，对于人ERβ,单一化合物表现出比OSU-ERβ-12更大的功能选择性。然而,像其他的间碳硼烷系列，其不良的体内药代动力学限制了其进一步开发的适用性。令人惊讶的是,与他们的药代动力学和体外人类活动数据不符，大多数类似物在雌激素幼稚的雌性小鼠中有效诱导子宫营养作用。对表达鼠雌激素受体的HEK293细胞的活性的进一步研究揭示了这些类似物的ER亚型选择性的物种特异性差异。我们的发现强调了物种特异性受体药理学及其在临床前物种中表征发育疗法所面临的挑战。意义陈述本研究调查了靶向雌激素受体的对和间取代的碳硼烷类似物，揭示了与小鼠同系物相比，碳硼烷类似物对人ERβ的选择性更大。这些发现揭示了在药物开发中使用临床前物种来预测人类药理学的复杂性。该报告还为完善和优化碳硼烷类似物作为雌激素相关疾病状态的潜在治疗剂提供了见解。
