Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Ghosh, Arun K.^1,2  Pandey, Satyendra^1,2  Gangarajula, Sudhakar^1,2  Kulkarni, Sarang^1,2  Xu, Xiaoming^1,2  Rao, Kalapala Venkateswara^1,2  Huang, Xiangping³  Tang, Jordan³ 

[1] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA

[2] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA

[3] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, Prot Studies Program, Oklahoma City, OK 73104 USA

关键词: beta-Secretase;    Alzheimer's disease;    Memapsin 2;    Inhibitor;    Design and synthesis;    Dihydroquinazoline;   

DOI  :  10.1016/j.bmcl.2012.07.043

来源: Elsevier

【 摘 要 】

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived beta-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K-i = 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 beta-secretase. The model suggested possible interactions in the active site. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free