In the last decade, advances in understanding the neurobiology of
Alzheimer's disease (AD) have translated into an increase in clinical trials assessing various potential AD treatments. At present, drugs used for the treatment of AD only slightly delay the inevitable symptomatic progression of the disease and do not affect the main neuropathological hallmarks of the disease, i.e.
senile plaques and neurofibrillary tangles. Brain accumulation of oligomeric species of
beta-amyloid (A beta)
peptides, the principal components of
senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being made to identify drugs able to interfere with
proteases regulating A beta formation from
amyloid precursor
protein (APP). Compounds that stimulate
alpha-secretase, the
enzyme responsible for non-amyloidogenic metabolism of APP, are being developed and one of these, EHT-0202, has recently commenced evaluation in a phase II study. The discovery of inhibitors of
beta-secretase (memapsin-2,
beta-amyloid cleaving
enzyme-1 [BACE-1]), the
enzyme that regulates the first step of amyloidogenic APP metabolism, has proved to be particularly difficult because of inherent medicinal chemistry issues and only one compound (CTS-21166) has proceeded to clinical testing. Conversely, several compounds that inhibit
gamma-secretase, the pivotal
enzyme that generates A beta, have been identified, the most advanced being LY-450139 (
semagacestat), presently in phase III clinical development. There has been considerable disappointment over the failure of a phase III study of
tarenflurbil, a compound believed to modulate the activity of
gamma-secretase, after encouraging phase II findings. Nevertheless, other promising
gamma-secretase modulators are being developed and are approaching clinical testing. All these therapeutic approaches increase the hope of slowing the rate of decline in patients with AD and modifying the natural history of this devastating disease within the next 5 years.