Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. Issue 15 (15th August 2018)

• Record Type: Journal Article
• Authors: Ghosh, Arun K.; Ghosh, Koena; Brindisi, Margherita; Lendy, Emma K.; Yen, Yu-Chen; Kumaragurubaran, Nagaswamy; Huang, Xiangping; Tang, Jordan; Mesecar, Andrew D.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 15(2018)
• Page Start: 2605
• Page End: 2610
• Publication Date: 2018-08-15
• Subjects: β-secretase -- Alzheimer's disease -- Memapsin 2 -- BACE-1 -- Isoxazoline; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.06.045
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: A series of BACE1 inhibitors incorporating bicyclic isoxazoline carboxamides as the P3 ligands is described. An X-ray crystal structure of 3a -bound BACE1 provided insight into the ligand-binding site interactions. Abstract: 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 Å resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature.