Details

Autor(en) / Beteiligte

• Zhao, Zhiqiang
• Pissarnitski, Dmitri A
• Josien, Hubert B
• Wu, Wen-Lian
• Xu, Ruo
• Li, Hongmei
• Clader, John W
• Burnett, Duane A
• Terracina, Giuseppe
• Hyde, Lynn
• Lee, Julie
• Song, Lixin
• Zhang, Lili
• Parker, Eric M

Titel

Discovery of a Novel, Potent Spirocyclic Series of γ‑Secretase Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 2015-11, Vol.58 (22), p.8806-8817

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer’s disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a­(−) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.