The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aβ42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aβ42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aβ42 levels in the plasma of J20 mice, in addition to reducing Aβ42 levels in the plasma and brain of Tg2576 mice.

介绍了通过引入新的杂环来调整活性以降低 Aβ42 水平和与类药物分子一致的特性的 γ-分泌酶调节剂 (GSM) 的演变。在四环支架内插入甲氧基吡啶基序为化合物提供了具有改善的阻止 Aβ42 产生的活性以及改善的特性，包括溶解性。体内药代动力学分析表明，新系列中的几种化合物能够穿过 BBB 并到达治疗靶点。除了降低 Tg2576 小鼠血浆和脑中的 Aβ42 水平外，用甲氧基吡啶衍生的化合物 64 处理还降低了 J20 小鼠血浆中的 Aβ42 水平。