Recent work (Krafft et al., Cell 2013) has demonstrated that amyloid beta oligomers are the synaptotoxic entity at the earliest stages of Alzheimer’s Disease. Acelot has identified novel brain-penetrant small molecule antagonists of synaptotoxic amyloid oligomer action.
Acelot has identified several families of potential oligomer antagonists via the JPS approach. These were tested in a high-quality neuronal assay that evaluates the “health” of neurons. Specifically, the assay measures amyloid-beta oligomer induced decreases in membrane trafficking in mature primary neuronal cultures.
The identified Acelot compounds show potent antagonist activity, some with nanomolar potency. This is a remarkable result, given that the exact mechanism-of-action is still being investigated and only membrane trafficking data were available as input to JPS. In addition, all Acelot compounds show a variety of novel structural scaffolds, opening new opportunities for the development of Alzheimer’s Disease cures with minimal side-effects.
All lead candidates are currently being tested in further in-vitro and in-vivo assays.
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(This work is funded in part by the National Science Foundation.)