Targeted Chemical Modification of BACE-1 Inhibitors: One Step Closer to the Prevention of Alzheimer’s Disease

Sara Yasrebi

Introduction. Alzheimer’s Disease is the 6th leading cause of U.S. deaths. and of the top 10, it is the only one without a known cause or cure.1 This age-related neurodegenerative disease is caused by the action of b-secretase (BACE-1) on APP instead of a-secretase, inducing the formation and deposition of pathogenic b-Amyloid plaques in neurons of the neocortex and hippocampus. These hallmark b-amyloid plaques thus cause progressive memory loss, personality changes and cognitive/motor impairment.2 Many clinical trials hoping to inhibit the pathologic action of BACE-1 enzyme have failed because their drugs interact with other enzymes such as BACE-2 and Cathepsin-D, inducing severe side effects. A study by Neumann et. all developed the drug CNP520 and chemically modified it to avoid these adverse interactions.3 Methods. CNP520 contains an amino-oxazine head group that has affinity for Asp-32 and Asp-228 of BACE-1, reducing its binding to BACE-2 and Cathepsin-D and preventing ocular toxicity.3 Trifluoromethyl groups were also added to encourage passage into the blood-brain barrier and it’s slightly-basic pH of 7.2 prevented CNP520 from traveling to peripheral areas and causing liver toxicity.3 Aniline groups were removed to prevent metabolically-induced gene destruction and its mutagenic effects.3 CNP520 was then tested on mice with b-amyloid plaque deposition.3 Brain biopsies showed a reduction in b-amyloid plaque area and immunohistochemistry targeted for microglia and astrocytes revealed a decrease in neuroinflammation with no ocular/hepatotoxicity within normal dose ranges.3 Five human studies, including a 3-month Phase IIa study, were also done on cognitively-normal and post-menopausal female subjects of age ranges 18-55 and ≥ 60 years.4 Results. A 750mg dose of CNP520 showed a maximum 79.1 ± 8.9% reduction of Ab40 plaque from baseline and a dose-dependent increase of non-amyloidogenic a-amyloid protein3. Additionally, enzyme inhibition assays confirmed that CNP520 was a potent and selective inhibitor of BACE-1 over other proteases such as BACE-2 and CatD. Replacement of aniline-type structures with fluoropyridyl moieties successfully avoided the risk of genotoxic aniline metabolites. An apical-to-basolateral transport rate of 6.6 x 10-6 cm/s indicated successful BBB permeation. Discussion/Conclusion. CNP520 proved to be successful at slowing the progression of Alzheimer’s Disease by dramatically reducing the formation of b-amyloid plaque. Additionally, its unique chemical structure allowed it to selectively inhibit BACE-1 and reduce ocular/hepatotoxicity, genotoxic effects, and drug efflux from the CSF. CNP520’s success has allowed it to progress into further clinical trials and shows promising effect as a revolutionary drug against Alzheimer’s Disease.4


  1. Alzheimer’s Disease and Dementia. (2019). Facts and Figures. [online] Available at:
  2. Shen Y, Wang H, Sun Q, et al. Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals with Mild Cognitive Impairment. Biol Psychiatry. 2017;83(5):447–455. doi:10.1016/j.biopsych.2017.02.007
  3. Neumann U, Ufer M, Jacobson LH, et al. The BACE‐1 inhibitor CNP520 for prevention trials in Alzheimers disease. EMBO Molecular Medicine. 2018;10(11). doi:10.15252/emmm.201809316.
  4. Lopez Lopez C, Caputo A, Liu F, Riviere ME, Rouzade‐Dominguez M‐L, Thomas RG,Langbaum JB, Lenz R, Reiman EM, Graf Aet al (2017) The Alzheimer’s prevention initiative generation program: evaluating CNP520 efficacy in the prevention of Alzheimer’s disease. J Prev Alzheimers Dis 4: 242–246