Discovery of Functionalized 1H-Benzodimidazoles That Confer Protective Effects in a Phenotypic CLN3 Disease Patient-Derived iPSC Model

The neuronal ceroid lipofuscinoses (NCLs) are rare and fatal autosomal pediatric neurodegenerative disorders. The most prevalent subtype, CLN3, arises from a mutation in the CLN3 gene. Common phenotypic hallmarks include lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and reduced Bcl-2 expression, however the underlying pathophysiology is not well understood. No effective treatment option exists. Herein, we report the synthesis and characterization of bicyclic analogues of the bioisosteric non-opioid analgesics Flupirtine and Retigabine, previously shown to exhibit neuroprotective effects. These analogues were strategically modified to prevent formation of toxic reactive diamine/diimine intermediates characteristic of the parent compounds. Novel 1H-benzodimidazoles that do not incur this metabolic liability are reported that possess enhanced protective effects in a highly phenotypic CLN3 patient-derived induced pluripotent stem cell (iPSC) model. Selected lead compounds 9b and 38b afforded significant protective effect and reduced phenotypic hallmarks of CLN3 pathology while also possessing "drug-like" pharmacokinetics.