Discovery of Functionalized 1 H-Benzo[ d]imidazoles That Confer Protective Effects in a Phenotypic CLN3 Disease Patient-Derived iPSC Model

J Med Chem. 2025 Sep 11;68(17):18530-18552. doi: 10.1021/acs.jmedchem.5c01369. Epub 2025 Sep 1.

Abstract

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-benzo[d]imidazoles 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.

MeSH terms

  • Drug Discovery*
  • Humans
  • Imidazoles* / chemical synthesis
  • Imidazoles* / chemistry
  • Imidazoles* / pharmacology
  • Induced Pluripotent Stem Cells* / drug effects
  • Induced Pluripotent Stem Cells* / metabolism
  • Membrane Glycoproteins* / genetics
  • Membrane Glycoproteins* / metabolism
  • Molecular Chaperones* / genetics
  • Molecular Chaperones* / metabolism
  • Neuronal Ceroid-Lipofuscinoses* / drug therapy
  • Neuronal Ceroid-Lipofuscinoses* / genetics
  • Neuronal Ceroid-Lipofuscinoses* / metabolism
  • Neuronal Ceroid-Lipofuscinoses* / pathology
  • Neuroprotective Agents* / chemical synthesis
  • Neuroprotective Agents* / chemistry
  • Neuroprotective Agents* / pharmacology
  • Phenotype
  • Structure-Activity Relationship

Substances

  • CLN3 protein, human
  • Molecular Chaperones
  • Membrane Glycoproteins
  • Neuroprotective Agents
  • Imidazoles