Drug Development for Alzheimer's Disease: Recent Progress

Abstract

Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development.

Amyloid Hypothesis: Is There a Role for Antiamyloid Treatment in Late-Life Depression?

“…The development of effective β-secretase inhibitors has been challenging because of the complex structure of the enzyme and the poor blood-brain barrier penetration of β-secretase inhibitors. Two β-secretase inhibitors, CTS-21166 and LY2811376, underwent phase I trials and showed dose-dependent reduction of amyloid (59). Another β-secretase inhibitor, MK-8931 was adequately tolerated and resulted in a dose dependent reduction of CSF Aβ levels in mild-to-moderate AD patients (60).…”

“…The γ-secretase inhibitor stemolecule lowered Aβ amyloid level in the brain of a mouse model (59). However, inhibition of γ-secretase has been associated with inhibition of vital substrates such as the Notch protein.…”

“…Tramiprosate binds to Aβ and reduces polymerization in vitro and Aβ brain depositions in animal models. While adequately tolerated, phase III trials failed to show cognitive improvement (59). …”

Alzheimer's disease clinical trials: past failures and future opportunities

“…The 5-HT 1A agonist xaliproden, thought to be neuroprotective, was found to decrease loss of hippocampal volume in two Phase III studies, but it lacked efficacy on cognitive endpoints [22]. The 5HT 4 agonist PRX-3140, 5HT 4 partial agonists such as PF04995275 and RQ-9 and 5-HT 6 antagonists including LU-AE58054, PRX-07034, PF-05212365, SR57746 and SB742457 may be in development [21,23].…”

“…These include the GABA-B antagonist SGS-742 and the phosphodiesterase-4 inhibitors MEM 1414 and MK-0952 [23]. Although FDA-approved and widely used for treatment of AD in the past, ergoloid mesylates, a combination of three dehydrogenated ergot alkaloids that may stimulate dopaminergic and serotofuture science group Alzheimer's disease clinical trials: past failures & future opportunities Clinical Trial Perspective nergic receptors, were unsuccessful in a pivotal trial [26].…”