Metachromatic leukodystrophy (MLD) is a rare, genetic lysosomal storage disorder caused by the deficiency of arylsulfatase A enzyme, which results in the accumulation of sulfatide in the lysosomes of the tissues of central and peripheral nervous systems, leading to progressive demyelination and neurodegeneration. Currently there is no cure for this disease, and the only approved therapy, hematopoietic stem cell transplant, has limitations. We proposed substrate reduction therapy (SRT) as a novel approach to treat this disease, by inhibiting ceramide galactosyltransferase enzyme (UGT8). This resulted in the identification of a thienopyridine scaffold as a starting point to initiate medicinal chemistry. Further optimization of hit compound 1 resulted in the identification of brain penetrable, orally bioavailable compound 19, which showed efficacy in the in vivo pharmacodynamic models, indicating the potential to treat MLD with UGT8 inhibitors.

中文翻译：

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用于治疗溶酶体贮积症的神经酰胺半乳糖基转移酶的脑可渗透抑制剂

异染性脑白质营养不良 (MLD) 是一种罕见的遗传性溶酶体贮积症，由芳基硫酸酯酶 A 酶缺乏引起，导致中枢和外周神经系统组织的溶酶体中硫苷脂积聚，导致进行性脱髓鞘和神经变性。目前还没有治愈这种疾病的方法，唯一获得批准的疗法，造血干细胞移植，也有局限性。我们建议通过抑制神经酰胺半乳糖基转移酶 (UGT8) 将底物还原疗法 (SRT) 作为治疗这种疾病的新方法。这导致噻吩并吡啶支架的鉴定作为启动药物化学的起点。命中化合物1 的进一步优化导致鉴定出脑可渗透、口服生物可利用的化合物19，其在体内药效学模型中显示出功效，表明使用 UGT8 抑制剂治疗 MLD 的潜力。