Nonclinical Characterization of ACP-204, a Novel Selective 5-HT2A Receptor Inverse Agonist

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Pimavanserin is an FDA-approved antipsychotic targeting 5-HT_2A receptors, but its use is limited by QT interval prolongation and a long half-life.
• Psychotic disorders, particularly in Alzheimer disease and Lewy body dementia, represent a significant unmet medical need with limited treatment options.

Purpose of the Study:

• To evaluate ACP-204, a novel 5-HT_2A receptor inverse agonist/antagonist, for its potential to treat psychosis associated with neurodegenerative conditions.
• To compare the safety and pharmacokinetic profile of ACP-204 with pimavanserin.

Main Methods:

• ACP-204 was assessed for receptor binding affinity, functional potency at 5-HT_2A and 5-HT_2C receptors, and selectivity against other targets.
• In vitro assays evaluated ACP-204's effect on cardiac ion channels (hERG, Cav1.2, Nav1.5).
• Efficacy was tested in rodent models of schizophrenia, and central 5-HT_2A engagement was studied in nonhuman primates. Pharmacokinetic and toxicity studies were conducted.

Main Results:

• ACP-204 demonstrated subnanomolar affinity and potency at 5-HT_2A receptors with high selectivity over 70 other targets.
• ACP-204 showed significantly lower potency for inhibiting cardiac ion channels compared to pimavanserin.
• The compound was orally active, effective in preclinical models, and predicted to have a shorter half-life (14.7-21.7 hours) in humans, suggesting improved dosing flexibility and faster steady-state achievement.

Conclusions:

• ACP-204 exhibits optimized pharmacodynamic properties, a favorable safety profile, and a broad therapeutic index.
• Its improved selectivity and reduced cardiac ion channel activity suggest a potential for greater dosing flexibility and tolerability compared to pimavanserin.
• ACP-204 is a promising candidate for treating psychosis in Alzheimer disease and Lewy body dementia.