BACE1 has a large catalytic site, and this has made it difficult to find small-molecule BACE1 inhibitors that can efficiently cross the blood-brain barrier and are still large enough to block the substrate-binding site of this enzyme. Remarkably, recent progress in medicinal chemistry has led to the development of selective and bioavailable BACE1 inhibitors, some of which have been advancing to phase II/III clinical trials in mild-to-moderate AD. Preclinical investigations of BACE1 inhibitors (e.g., GRL-8234 and TAK-070) successfully reveal mnemonic improvements concomitant with significant cerebral Aβ reduction in the Tg2576 mouse model of AD following systemic administration if the treatment is started during the relatively earlier or pre-pathological phase. In this study investigators compared the effects of the potent and selective small-molecule BACE1 inhibitor GRL-8234 in different pathological stages of the 5xFAD mouse model. GRL-8234 was administered once daily, from 2 months to 4 month age (with modest Abeta pathology) and 10 month (with massive Abeta pathology) 5xFAD mice. The data show that chronic administration of GRL-8234 has beneficial effects on amyloidosis and memory deficits in 5XFAD mice if the treatment is initiated during earlier, but not advanced stages of Abeta accumulation. In 12-month-old 5XFAD mice treated with GRL-8234 only marginal reductions of Aβ42 were observed and their memory function remained impaired. Importantly, the authors reported that BACE1 and full-length APP expression were significantly elevated older 5XFAD mice with progressive Aβ accumulation; GRL-8234 treatment failed to affect these detrimental mechanisms that are predicted to further accelerate beta amyloid plaque deposition. Results suggest that a combination of the BACE1 inhibitor and agents that block BACE1-elevating pathways, could lower APP expression or remove Abeta plaques, (e.g., passive immunization), and may provide a more efficacious and safe strategy to treat memory deficits in AD with established amyloid pathology.
For PK properties of GRL-834 see the following: Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, et al. β-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J. 2011; 25:775–784. [PubMed: 21059748].