Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent ¦Â-secretase inhibitors
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- 作者：Arun K. Ghosh ; Satyendra P ; ey ; Sudhakar Gangarajula ; Sarang Kulkarni ; Xiaoming Xu ; Kalapala Venkateswara Rao ; Xiangping Huang ; Jordan Tang
- 关键词：¦Â-Secretase ; Alzheimer&rsquo ; s disease ; Memapsin 2 ; Inhibitor ; Design and synthesis ; Dihydroquinazoline
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：1 September, 2012
- 年：2012
- 卷：22
- 期：17
- 页码：5460-5465
- 全文大小：1678 K
文摘
Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived ¦Â-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (Ki = 13 nM) and cellular (IC50 = 21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound ¦Â-secretase. The model suggested possible interactions in the active site.