Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease

Area of Science:

• Neuroscience
• Medicinal Chemistry
• Pharmacology

Background:

• Alzheimer's disease (AD) is a complex neurodegenerative disorder with urgent therapeutic needs.
• Current AD treatments are limited, necessitating novel therapeutic strategies.
• Multitarget-directed ligands offer a promising approach for complex diseases like AD.

Purpose of the Study:

• To design, synthesize, and evaluate novel multitarget compounds for Alzheimer's disease (AD) treatment.
• To develop ligands combining H3 receptor (H3R) antagonism and acetylcholinesterase (AChE) inhibition.
• To identify a lead compound for further preclinical investigation.

Main Methods:

• Synthesis of novel compounds merging sulfonylurea and pitolisant structural motifs.
• In vitro evaluation of H3R binding affinity and AChE inhibitory activity.
• Assessment of acetylcholine release and in vivo cognitive effects in a scopolamine-induced model.

Main Results:

• Eight compounds exhibited H3R binding activity and moderate AChE inhibition.
• Two compounds (derivatives 2 and 7) increased acetylcholine release in vitro.
• Compound 2 reversed scopolamine-induced cognitive deficits in vivo, comparable to galantamine.
• Compound 2 showed moderate in vitro blood-brain barrier (BBB) permeation.

Conclusions:

• The designed multitarget compounds represent a novel strategy for AD drug discovery.
• Compound 2 is a promising lead candidate for further medicinal chemistry optimization.
• The fragment-like nature of compound 2 supports its potential as a starting point for AD therapeutics.