Anavex Life Sciences Corp., (Anavex) provides a summary of its second poster presentation at the Alzheimer’s Association International Conference (AAIC) held in Paris, entitled & ldquoPreclinical development of new tetrahydrofuran derivatives targeting the sigma-1 chaperone protein as neuroprotectants in Alzheimer’s disease.
Neuroprotective, anti-amnesic, anti-depressive and anti-convulsive effects have previously been described with a new class of a wholly owned family of compounds, the aminotetrahydrofurans. In this study, two of the leads from this family, ANAVEX 2-73 and ANAVEX 1-41, were studied for their anti-amnesic and neuroprotective effects. These compounds are mixed sigma-1 agonists and also have cholinergic effects.
In some respects, the authors claim, these compounds could be compared to donepezil, which is the market leader in Alzheimer’s disease (AD) medication. Donepezil also happens to be a partial sigma-1 agonist as well as exerting its well-known cholinergic effects. In addition, the metabolites for both ANAVEX 2-73 and 1-41 were identified and also studied for any effect.
Utilizing a well-known model that mimics AD by injecting oligomeric amyloid 25-35 fragments into the brain of rodents, the researchers found that: ANAVEX 2-73 showed prevention and reversal biochemically, histologically and behaviourally. It reverses amyloid 25-35-induced amnesia in mice. It is when administered prior to amyloid 25-35, protects against amyloid 25-35-induced amnesia in mice. ANAVEX 2-73 protects against amyloid 25-35-induced oxidative stress, measured by lipid peroxidation in hippocampal cells, a key area of the brain associated with learning and memory. It protects against amyloid 15-35-induced hippocampal cell loss.
ANAVEX 1-41 also demonstrates similar effects, but is not as selective for sigma receptors as ANAVEX 2-73. ANAVEX 2-73 is not only active in and of itself, but is also a pro-drug. Its only metabolite, ANAVEX 19-144, is also active in these animal models. The metabolite of ANAVEX 1-41, ANAVEX 2-140, does not display such activity.
ANAVEX 19-144, when administered prior to amyloid 25-35, protects against amyloid 25-35-induced amnesia in mice. ANAVEX 19-144 protects against amyloid 25-35-induced oxidative stress, measured by lipid peroxidation in hippocampal cells.
“It is hypothesized that cholinomimetic-only compounds would not have as much benefit as the mixed mechanism of the aminotetrahydrofurans, which may be potentiating. Interestingly, the pro drug and active drug effect of ANAVEX 2-73, which has ANAVEX 19-144 ’embedded’ in it, may offer a longer duration of action”, said Dr Tangui Maurice, PhD, CNRS Research Director, Team II Endogenous Neuroprotection in Neurodegenerative Diseases INSERM, University of Montpellier, one of the poster authors and a member of the Anavex Scientific Advisory Board. “Histological evidence is powerful visible evidence of neuroprotection and this study also reinforces the anti-amnesic effects already described in this animal model of amyloid toxicity benefit with aminotetrahydrofurans.”
“We are excited to have had this, as well as a poster on ANAVEX 2-73 and a potential dual role in amyloid and tau, accepted at such a prestigious event as AAIC”, said Dr Cameron Durrant, executive chairman of Anavex. “These neuroprotection data may translate into clinical studies as we continue to explore disease-modifying approaches with our novel family of compounds and the lead small molecule, ANAVEX 2-73. It may be potentially beneficial to have a further positive effect on top of ANAVEX 2-73 in the form of its active metabolite ANAVEX 19-144. We eagerly await results from the ANAVEX 2-73 phase I clinical trial, which is scheduled for completion soon.”
AAIC (formerly ICAD, the International Conference on Alzheimer’s Disease) is the largest gathering of researchers, clinicians and other stakeholders in Alzheimer’s disease. This year, the conference drew a record-breaking number of dementia scientists to Paris to share the latest ideas, thoughts and theories in the field. Breaking studies captured global media attention as the world’s leading experts explored innovative ways to further Alzheimer’s research. For more information, please visit Alzheimer’s Association web site.
This phase I clinical trial is a randomized, placebo-controlled study to initially test ANAVEX 2-73 as a single, ascending oral dose in healthy male volunteers between the ages of 18 and 55. The trial seeks to determine the maximum tolerated single dose, safety and pharmacokinetics.
The phase I clinical trial is being conducted in Germany in collaboration with ABX-CRO, a clinical research organization that has conducted several Alzheimer’s disease studies, and the Technical University of Dresden.