Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation

Alzheimer's disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where beta-amyloid structures (A beta) build toxic oligomers. Design of disease modifying multi target directed ligand (MTDL) has been performed, which disable PPI on the one hand and on the other hand, act as procognitive antagonists at the histamine H-3 receptor (H3R). The synthetized compounds are structurally based on peptidomimetic amino acid-like structures mainly as keto, diketo-, or acyl variations of a piperazine moiety connected to an H3R pharmacophore. Most of them showed low nanomolar affinities at H3R and some with promising affinity to A beta-monomers. The structure-activity relationships (SAR) described offer new possibilities for MTDL with an optimized profile combining symptomatic and potential causal therapeutic approaches in AD.

Automated summary

Researchers have designed disease-modifying ligands that target multiple pathways in Alzheimer's disease, both disabling protein-protein interactions and acting as cognitive enhancers at the H3R receptor. These synthesized compounds show low nanomolar affinities at H3R, with some demonstrating promising interactions with A beta monomers. The structure-activity relationships described provide new avenues for developing multi-target compounds with optimized profiles for AD treatment.