Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Ghosh, Arun K.^1,2  Ghosh, Koena¹  Brindisi, Margherita¹  Lendy, Emma K.³  Yen, Yu-Chen⁴  Kumaragurubaran, Nagaswamy¹  Huang, Xiangping⁵  Tang, Jordan^5,6  Mesecar, Andrew D.^1,3,4 

[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 Biochem, W Lafayette, IN 47907 USA

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

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

[6] 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;    Isoxazoline;   

DOI  :  10.1016/j.bmcl.2018.06.045

来源: Elsevier

【 摘 要 】

We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 K(i)value of 10.9 nM and EC50 of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 A resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.

【 授权许可】

Free