Alzheimer’s disease (AD) continues to be a significant unmet medical need. According to the CDC, in 2015, AD was the 5th leading cause of disease-related deaths in people over age 65. Current therapies such as Aricept (donepezil), Namenda (memantine), and Razadyne (galantamine) are palliative treatments that slow cognitive decline by regulating neurotransmitters, but there are no clinically approved disease modifying therapies for the treatment of AD. The lack of valid targets is a major factor contributing to the paucity of available AD treatments. One of the early hypotheses on the pathophysiology of AD stated that the formation of Aβ protein plagues and Tau protein tangles resulted in synaptotoxicity in neurons leading to significant cognitive defects. An alternative hypothesis, the oligomer hypothesis of AD, states that soluble Aβ oligomers (AβOs) are the pathogenic agent in AD. According to this theory, AβOs bind specifically and saturably to a receptor site on neurons, rapidly inhibiting long term potentiation (LTP) by altering glutamate receptor trafficking to the plasma membrane. This leads to a transient synaptic spine regression and inhibition of learning and memory. Recent published work has strongly supported the oligomer hypothesis via demonstrating that the sigma-2/PGRMC1 (sigma-2) receptor modulates the binding of AβO to receptors on neurons and that this protein can be targeted with small molecules to inhibit the binding and synaptotoxic effects of AβOs. This study established that small molecules directed towards the sigma-2/PGRMC1 receptor can prevent and displace binding of Aβ oligomers to neurons. These first-in–class small molecule drug candidates blocked downstream synaptotoxicity and restored memory in aged transgenic mouse models of AD. Recently, we have identified a novel series of sigma-2 binders that have the significant potential for further advancement as part of drug discovery program. To date, over 100 compounds have been prepared in this new series, and many examples exhibit potent sigma-2 binding (IC50 &lt; 100nM). The synthesis, biological activity and in vitro ADME of this series will be discussed.

Design, synthesis, and in vitro evaluation of novel sigma-2 receptor modulators: An opportunity in Alzheimer’s disease therapy

253rd National Meeting (2017)

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