Dual 5-HT 2A and 5-HT 2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin ( 1 ), a 5-HT 2A receptor inverse agonist having minimal 5-HT 2C receptor affinity and no dopamine D 2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT 2A and 5-HT 2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT 2A and 5-HT 2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT 2A and 5-HT 2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT 2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.