Background:

Usmarapride (SUVN-D4010) is a potent, selective and orally bioavailable 5-HT₄ receptor partial agonist being developed for the treatment of cognitive disorders.

Methods:

The procognitive properties of Usmarapride were evaluated across multiple preclinical models of cognition, including the object recognition task, radial arm maze, and contextual fear conditioning. Neurotransmitter modulation was investigated using brain microdialysis. The in-vivo receptor binding profile was assessed in rats using a non-radiolabeled tracer. Additionally, the effects of Usmarapride on biomarkers such as sAPP and BDNF were quantified using ELISA. The safety, tolerability, and pharmacokinetic profile of Usmarapride was evaluated in healthy human subjects.

Results:

Usmarapride ameliorated episodic memory deficits in the object recognition task and reversed scopolamine-induced impairments in working and emotional memory in the radial arm maze and fear conditioning assays. Oral administration of Usmarapride significantly increased brain acetylcholine levels, and its procognitive and cholinergic effects were blocked by GR-125487, a selective 5-HT₄ receptor antagonist, confirming 5-HT₄-mediated activity. Consistent with this mechanism, Usmarapride demonstrated significant 5-HT₄ receptor occupancy at pharmacologically effective doses.

Treatment with Usmarapride resulted in a significant increase in cortical sAPPα and BDNF levels, along with a reduction in amyloid-β protein levels, indicating neuroprotective effects. Furthermore, Usmarapride was found to be safe and well tolerated in healthy subjects and exhibited a favorable pharmacokinetic profile, supporting its continued clinical development.

Conclusions:

Usmarapride is a novel, potent, selective, orally bioavailable, efficacious, and safe 5-HT₄ receptor partial agonist. Nonclinical and clinical studies conducted to date demonstrate its promising therapeutic potential which warrants its further evaluation. A proof-of-concept Phase 2 study, in concurrence with the FDA, is currently being planned.