Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Ghosh, Arun K.^1,2,3  Brindisi, Margherita^1,2  Yen, Yu-Chen⁴  Xu, Xiaoming^1,2  Huang, Xiangping^1,5  Devasamudram, Thippeswamy^3,6  Bilcer, Geoffrey^3,6  Lei, Hui⁶  Koelsch, Gerald^1,5,6  Mesecar, Andrew D.^1,4  Tang, Jordan^1,5,7 

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

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

[3] Univ Illinois, Dept Chem, Chicago, IL 60607 USA

[4] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA

[5] Oklahoma Med Res Fdn, Prot Studies Program, Oklahoma City, OK USA

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

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

关键词: beta-secretase;    Alzheimer's disease;    Memapsin 2;    BACE-1;    Protease inhibitors;   

DOI  :  10.1016/j.bmcl.2014.11.087

来源: Elsevier

【 摘 要 】

We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-beta-amino-L-alanine as a novel P2 ligand. A number of inhibitors have displayed b-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, K-i = 0.25 nM, cellular EC50 of 194 nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound beta-secretase which revealed critical interactions in the active site. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

Free