Details

Autor(en) / Beteiligte

• Zhao, Zhiqiang
• Pissarnitski, Dmitri A.
• Josien, Hubert B.
• Bara, Thomas A.
• Clader, John W.
• Li, Hongmei
• McBriar, Mark D.
• Rajagopalan, Murali
• Xu, Ruo
• Terracina, Giuseppe
• Hyde, Lynn
• Song, Lixin
• Zhang, Lili
• Parker, Eric M.
• Osterman, Rebecca
• Buevich, Alexei V.

Titel

Substituted 4-morpholine N-arylsulfonamides as γ-secretase inhibitors

Ist Teil von

• European journal of medicinal chemistry, 2016-11, Vol.124, p.36-48

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-β (Aβ) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD). [Display omitted] •γ-Secretase inhibitors arrest formation of amyloid-β, which plays a role in Alzheimer's disease.•Scissile carbamate bond of a known inhibitor was replaced with the non-scissile carboncarbon bond.•The effect of introduction of polarity (oxygen atoms) in various parts of molecule has been studied.•Stability and potency of the series was improved, while CYP3A4 inhibition was mitigated.