Batten disease is a rare, autosomal recessive neurodegenerative disorder, affecting around 1 in 12,500 children in the US. It is the most common form of a group of disorders called neuronal ceroid lipofuscinosis (NCLs). Various genes have been identified (CLN1-14) in which mutations can lead to Batten disease. However, the common pathway underlying these genes and their resulting proteins has not yet been identified. Currently, there is no cure for Batten disease; stem cell, gene therapy and enzyme replacement therapy have been attempted but failed to show efficacious results. Current treatment is symptomatic and supportive but does not target the underlying disease, accelerated rate of death of neurons.<br/>We and our collaborators have shown that the small molecule Flupirtine exerts neuroprotective effect in both isolated neurons and crucially, in Batten Disease patient lymphoblasts under pro-apoptotic conditions. Flupirtine was never designed as an NCL treatment, yet indicates potential in this disease state. No medicinal chemistry structure-activity relationship (SAR) studies have been conducted to investigate the potential of this compound as a hit for Batten disease.<br/>We have established a synthetic route suitable for the generation of diverse analogues of flupirtine to permit SAR determination of neuroprotective activity. Our preliminary screening in PC12 cells have identified several analogues which provide enhanced neuroprotective effect as compared to flupirtine. These results translate to SH-SY5Y cells, human neurons differentiated from iPSCs and NCL phenotypic siRNA knockdown PC12 cells. We have demonstrated that the lead molecules act, at least in part, by upregulating the antiapoptotic protein Bcl-2. Appendage of affinity-capable moieties to these enhanced activity compounds will provide chemical probes to allow identication of protein targets.

Design, synthesis and employment of Flupirtine-derivative chemical probes for neuroprotective target identification

253rd National Meeting (2017)

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