The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound 1 led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved in vitro safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor 11 demonstrated strong in vivo target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound 11 enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.

中文翻译：

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增强少突胶质细胞形成的选择性脑渗透 EBP 抑制剂的发现和优化

emopamil 结合蛋白 (EBP)（胆固醇生物合成途径中的一种甾醇异构酶）的抑制可促进少突胶质细胞的形成，这已被提议作为治疗多发性硬化症的潜在治疗方法。在此，我们描述了脑渗透性、口服生物可利用的 EBP 抑制剂的发现和优化。基于文献化合物1的基于结构的药物设计方法导致了基于乙内酰脲的支架的发现，该支架提供了平衡的理化性质和效力以及改进的体外安全性。早期基于乙内酰脲的 EBP 抑制剂在啮齿类动物中的半衰期较长，催生了一种非常规的优化策略，重点是增加代谢周转，同时保持效力和脑渗透特性。由此产生的 EBP 抑制剂11在大脑中表现出强大的体内靶点参与作用，如重复给药后 EBP 底物酵母烯醇的积累所示。此外，化合物11增强了人类皮质类器官中少突胶质细胞的形成，为我们的治疗假设提供了额外的支持。