Disease-modifying approach to the treatment of alzheimers disease: From α-secretase activators to γ-secretase inhibitors and modulators

In the last decade, advances in understanding the neurobiology of Alzheimers 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 β-amyloid (Aβ) 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 Aβ formation from amyloid precursor protein (APP). Compounds that stimulate α-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 β-secretase (memapsin-2, β-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 γ-secretase, the pivotal enzyme that generates Aβ, 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 γ-secretase, after encouraging phase II findings. Nevertheless, other promising γ-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.