Synthesis, Structure–Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5‑HT₄ Receptor Partial Agonists

Alzheimer’s disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT₄ receptor (5-HT₄R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT₄R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure–activity relationships, compound 4o was identified as a potent 5-HT₄R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT₄R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.