SUN13837 (1), a fibroblast growth factor receptor modulator, has been an attractive candidate for treating neurodegenerative diseases. However, one of its metabolites, N-benzyl-4-(methylamino)piperidine (BMP), turned out to possess phospholipidosis-inducing potential (PLIP) in vitro. To obtain SUN13837 analogs with reduced phospholipidosis risk, we replaced BMP with other diamines possessing low PLIP. Our effort led to the discovery of compound 6 with increased efficacy. Further structural modifications to reduce hydrogen bond donors afforded 17 with improved brain exposure. Oral administration of 17 at 1 mg/kg once daily for 10 days showed enhanced recovery of coordinated movement in a rat acute stroke model, suggesting that it is a promising follow-up compound for 1 with reduced risk of phospholipidosis.

SUN13837（1）是一种成纤维细胞生长因子受体调节剂，一直是治疗神经退行性疾病的诱人候选物。然而，其代谢物之一，N-苄基-4-（甲基氨基）哌啶（BMP），在体外具有诱发磷脂病的潜能（PLIP）。为了获得具有降低的磷脂病风险的SUN13837类似物，我们用具有低PLIP的其他二胺替代了BMP。我们的努力导致发现具有增强功效的化合物6。减少氢键供体的进一步结构修饰为17的大脑暴露提供了改善。口服17以1mg / kg的每日一次持续10天表现出增强的在大鼠急性中风模型协调运动的恢复，这表明它是有希望的后续化合物1与磷脂质的风险降低。