Alzheimer’s disease (AD) is a devastating neurological disease with no known cure. We are investigating a small molecule, Alaproclate, which was identified through screening by the Drug Discovery Laboratory, and its analogues as potential drug candidates to treat the disease. Alaproclate was shown to increase the neuroprotective SirT1 in the presence of the ApoE4 allele– a major risk factor for AD. We describe herein the design and synthesis of several analogs, and study their effects on two proteins associated with AD – the neuroprotective protein Sirtuin T1 (SirT1) and the neurotoxic protein Sirtuin T2 (SirT2) in an ApoE4 transfected neuronal model. We have identified analogs that have been shown to upregulate SirT1 expression while not affecting the SirT2 expression. We are carrying out additional assays with the active analogs involving the signaling networks affected by AD, along with pharmacokinetic (PK) studies to determine brain permeability. From the small library of synthesized analogues, we hope to find a lead compound that will help treat AD.

Development of a drug candidate for Alzheimer's disease

251st National Meeting (2016)

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