Discovery of amide and heteroaryl isosteres as carbamate replacements in a series of orally active γ-secretase inhibitors
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- 作者：Mark D. McBriar ; John W. Clader ; Inhou Chu ; Robert A. Del Vecchio ; Leonard Favreau ; William J. Greenlee ; Lynn A. Hyde ; Amin A. Nomeir ; Eric M. Parker ; Dmitri A. Pissarnitski ; Lixin Song ; Lili Zhang
- 关键词：γ ; -Secretase ; Alzheimer’ ; s disease
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2008
- 出版时间：1 January 2008
- 年：2008
- 卷：18
- 期：1
- 页码：215-219
- 全文大小：252 K
文摘
The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of γ-secretase inhibitors. Selected compounds showed significant reduction of Aβ levels upon oral dosing in a transgenic murine model of Alzheimer’s disease.