Design, synthesis, and X-ray structural studies of BACE-1 inhibitors containing substituted 2-oxopiperazines as P1′-P2′ ligands

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Ghosh, Arun K.^1,2  Brindisi, Margherita¹  Yen, Yu-Chen³  Cardenas, Emilio L.¹  Ella-Menye, Jean -Rene¹  Kumaragurubaran, Nagaswamy¹  Huang, Xiangping⁴  Tang, Jordan^4,5  Mesecar, Andrew D.^1,3,6 

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

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

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

[4] Oklahoma Med Res Fdn, Prot Studies Program, 825 NE 13th St, Oklahoma City, OK 73104 USA

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

[6] Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USA

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

DOI  :  10.1016/j.bmcl.2017.04.011

来源: Elsevier

【 摘 要 】

We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6 substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (K-i = 2 nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor 6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23 nM and cellular EC50 of 80 nM. (C) 2017 Elsevier Ltd. All rights reserved.

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