Local Research

A novel oral treatment for a deadly neurodegenerative disease, juvenile NCL or CLN3 disease. Are Flupirtine analogues neuroprotective in the NCLs or Batten disease?

Fady Saade Med III; Karl Mansour, Joelle Makoukji PhD; Paul Trippier PhD and Rose-Mary Boustany MD.

Batten disease or the neuronal ceroid lipofuscinoses (NCL) comprise a group of fatal inherited neurodegenerative diseases with no cure afflicting children from birth to early adulthood. Progressive deterioration leads to blindness, seizures, dementia, spasticity and death by the teens/early twenties. There is a critical need to develop new therapeutic agents that demonstrate activity to combat these diseases. A small molecule approved for use as a non-opioid analgesic, Flupirtine, has been shown to be neuroprotective in cellular models of NCL. Despite these initial observations and potential no further studies have been performed. This research has initiated a medicinal chemistry-driven drug discovery process using Flupirtine as a lead compound. The hypothesis of this application is that novel small molecule derivatives of Flupirtine significantly ameliorate neuronal apoptosis in NCL by upregulation of the apoptosis suppressor Bcl-2 and down-regulation of the lipid second messenger, ceramide. Detailed structure-activity relationship studies have led to identification of the pharmacophore of the lead structure in the hope of optimizing neuroprotective properties of analogues. The Trippier group provides medicinal chemistry expertise in collaboration with the Boustany group who are determining activity of synthesized compounds. Bioactivity results will determine future compound synthesis through rational drug design methods underlying the two interlinked aims of this application – the generation of novel compounds, and the determination of activity in cellular models of NCL, and ultimately, animal models.

The ultimate aim of this application is the generation of small molecules possessing enhanced neuroprotective activity in cellular models of NCL that retain good drug-like properties. Such compounds represent valuable preclinical therapeutic candidates requiring further evaluation. This application would be expected to form the basis of further research applications and experiments to perform preclinical and animal studies upon the most active compounds identified herein.

Nine neuroprotective flupirtine maleate analogues have been synthesized and structure-activity relationships to enhance activity determined.  Bioassays in human cells were carried out and the three best analogues were selected for further testing in NCL disease cell and animal models.