Potent memapsin 2 (β-secretase) inhibitors:: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:18

Article

Ghosh, Arun K.¹  Kumaragurubarana, Nagaswamy¹  Hong, Lin^2,3  Kulkarni, Sarang¹  Xu, Xiaoming¹  Miller, Heather B.¹  Reddy, Dandepally Srinivasa¹  Weerasena, Vajira²  Turner, Robert²  Chang, Wanpin³  Koelsch, Gerald^2,3  Tang, Jordan^3,4 

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

[2] CoMentis Inc, Oklahoma City, OK 73104 USA

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

[4] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73104 USA

关键词: Alzheimer;    design;    synthesis;    inhibitor;    memapsin 2;    beta-secretase;   

DOI  :  10.1016/j.bmcl.2007.12.028

来源: Elsevier

【 摘 要 】

Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic P-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K-i 1.8 nM) and cellular (IC50 = 1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site. (C) 2007 Elsevier Ltd. All rights reserved.

【 授权许可】

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