Histamine H3 receptor antagonists with peptidomimetic (keto)piperazine structures to inhibit Aβ oligomerisation. (15th November 2021) - Falkenstein, Markus
Graphical abstract: Highlights: New highly potent histamine H3 receptor ligands with SAR. Peptidomimetic elements for protein–protein interactions. New multiple targeting concept with inhibition of beta amyloid fragments and precognitive histamine H3 receptor ligands. New approach for the simultaneous symptomatic and causal treatment of neurodegenerative diseases like Alzheimeŕs disease by combination of GPCR and peptide attack. Abstract: Alzheimeŕs disease (AD) is the most prominent neurodegenerative disorder with high medical need. Protein-protein-interactions (PPI) interactions have a critical role in AD where β-amyloid structures (Aβ) 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 H3 receptor (H3 R). 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 H3 R pharmacophore. Most of them showed low nanomolar affinities at H3 R and some with promising affinity to Aβ-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.