Riluzole‐Derived Benzo[d]thiazoles as CK1 δ Inhibitors for Amyotrophic Lateral Sclerosis‐Related Neurodegeneration

Riluzole‐derived benzo[d]thiazoles were investigated as metabolite‐inspired CK1 δ inhibitors, a kinase involved in TDP‐43 phosphorylation and therefore relevant to amyotrophic lateral sclerosis (ALS). Starting from the known CK1 δ activity of riluzole, we examined whether its major hydroxylamine metabolite could preserve target recognition and provide a rational entry point for scaffold optimisation. The metabolite retained CK1 δ inhibition, but its limited chemical stability and toxicity in neuronal cells identified the hydroxylamine group as a critical liability. Replacement of this functionality with a hydrazine converted the fragile metabolite‐derived structure into a more potent and tractable CK1 δ inhibitor series. Structure–activity relationship studies revealed that the hydrazine moiety accommodates broader substitution than the hydroxylamine counterparts, with branched alkyl and benzyl groups giving the most balanced profiles. Docking and molecular dynamics suggested that the improvement could be attributed to an additional hydrogen‐bond with Gly86 in the hinge region. The best derivative combined submicromolar CK1 δ inhibition with passive blood–brain barrier permeability, short‐term cellular tolerance, ATP competitive inhibition, direct target engagement, and preliminary selectivity over GSK3β. Although this compound did not result neuroprotective in an oxidative stress model, it paves the way for a focused benzo[d]thiazole platform for probing CK1 δ biology in ALS.