Discovery of novel scaffolds for γ-secretase modulators without an arylimidazole moiety

Publication date: Available online 2 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ryuichi Sekioka, Eriko Honjo, Shugo Honda, Hideyoshi Fuji, Hiroki Akashiba, Yasuyuki Mitani, Shingo Yamasaki
Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-β 42 (Aβ42) and may therefore be useful in the management of Alzheimer's disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aβ42 (IC50 = 7.1 µM) without changing total production of Aβ. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aβ42 (IC50 = 0.39 µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.

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