Design, synthesis, and X-ray structural studies of BACE-1 inhibitors containing substituted 2-oxopiperazines as P1′-P2′ ligands. Issue 11 (1st June 2017) - Ghosh, Arun K.
Graphical abstract: A series of BACE1 inhibitors incorporating mono- and bicyclic 2-oxopiperazines is described. Inhibitor5a showed an enzyme K i of 2 nM and a cellular EC50 value of 3.5 nM. An X-ray structural analysis of a related compound5g -bound BACE1 provided insight into the ligand-binding site interactions. Abstract: 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, inhibitor5a with N -benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity ( K i = 2 nM). Inhibitor5g, with N -benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of5g -bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated. Inhibitor6j with an oxazolidinone derivative showed a BACE1 inhibitory activity of 23 nM and cellular EC50 of 80 nM.