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P2‐499: Safety and efficacy results of a phase II randomized, placebo‐controlled, dose‐ranging study of elnd005 (scyllo‐inositol) in mild‐to‐moderate Alzheimer's disease
Author(s) -
Salloway Stephen,
Porsteinsson Anton,
Sperling Reisa,
Keren Ron,
Dyck Christopher,
Tariot Pierre,
Gilman Sid,
Crans Gerald,
Hernandez Ramon,
Quinn Grainne,
Bairu Menghis,
Cedarbaum Jesse,
Pastrak Aleksandra,
Abushakra Susan
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1371
Subject(s) - placebo , medicine , discontinuation , clinical endpoint , adverse effect , randomized controlled trial , gastroenterology , pathology , alternative medicine
compound on excitatory synapses were investigated in 18 day in vitro (DIV) primary hippocampal neuronal cultures. The pharmacokinetic profile, including bioavailability and BBB penetration, were established in mice following oral and intravenous administration using a combined liquid chromatographymass spectrometry (LC-MS) approach.Results:Our screen has identified the lead compound dubbed ARN 4261, [(E)-2-(pyridin-2-ylmethyleneamino) phenol; MW1⁄4198.2Da], which is not toxic and at lowmicromolar concentration shows strong effects against both oligomerization and fibrillization of synthetic Aß peptide. Treatment of primary hippocampal neurons exposed to Aß with ARN4261 restored loss of synaptic proteins expression caused by Aß oligomers. We have subsequently modified the structure of ARN 4261 producing ARN 2966 (2-[(pyridine-2-ylmethyl)-amino]-phenol) which shows comparable anti-aggregation potency to ARN 4261, but it is more stable in acidic environment, hence it is suitable for oral administration. Pharmacokinetic experiments in mice showed that t1/2 of ARN 2966 is 6.13hr and 64.2% of orally administered dose is absorbed from the alimentary tract and passes the portal circulation. Preliminary studies show that ARN 2966 penetrates the BBB after oral and intravenous administration. Conclusions: Pyridin-2-ylmethylamine derivatives are a class of novel promising AD therapeutics. They are non toxic, have strong anti-Aß aggregation and neuroprotective properties and can be easily modified chemically for enhanced oral bioavailability and BBB penetration. Experiments in AD transgenic mice characterizing their effect on AD pathology in vivo are currently ongoing.