Design and synthesis of novel methoxypyridine-derived gamma-secretase modulators

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of A beta 42 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 A beta 42 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 A beta 42 levels in the plasma of J20 mice, in addition to reducing A beta 42 levels in the plasma and brain of Tg2576 mice.