Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors

Abstract

The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and >100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma Abeta40 measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).

Computational Methods in Drug Discovery

“…The binding site predicted to be deep within the binding pocket was consistent with mutagenesis studies. QXP has been used to optimize inhibitors of human b-secretase (BACE1) (Malamas et al, 2009(Malamas et al, , 2010Nowak et al, 2010), which is an important therapeutic target for treating Alzheimer's disease by diminishing b-amyloid deposit formation. ICM was used successfully to identify inhibitors for a number of targets, including tumor necrosis factor-a (Chan et al, 2010), dysregulation of which is implicated in tumorigenesis and autoinflammatory diseases like Computational Methods in Drug Discovery rheumatoid arthritis and psoriatic arthritis.…”

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

“…High throughput hit compound 120 (Figure 57) was found to bind to BACE1 with the flap in a more open position. 267 With the objectives of improving metabolic stability and to reduce polar total surface area of inhibitors, compound 121 was developed with an IC 50 of 20 nM. Further optimization provided compound 122 showing a low nanomolar inhibitor with a pIC 50 value of 7.5.…”

“…Compound 123 , with a spirocyclic cyclobutane moiety, showed an IC 50 of 10 nM. 269 Further optimization resulted in a series of BACE1 inhibitors with moderate to good potency. 270-275 …”

Heterocycles in Peptidomimetics and Pseudopeptides: Design and Synthesis

“…Actually many lines of research are concerned with the synthesis and study of small-molecule-containing heterocyclic rings as β-secretase inhibitors [36,37] (Figure 5b).…”