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

Pimavanserin was the first FDA–approved antipsychotic drug that does not block D 2 dopamine receptors at therapeutic doses. Pimavanserin is a selective 5-HT 2A receptor inverse agonist that reduces the frequency of hallucinations and delusions associated with Parkinson's disease. Despite these attributes, pimavanserin prolongs the QT interval at therapeutic doses, limiting the dose to 34 mg. In addition, pimavanserin has a 57-h half-life, and reaches steady state in approximately 12 days. ACP-204 was identified as a compound with sub-nanomolar affinity in radioligand binding assays, and sub-nanomolar inverse agonist and antagonist potency at 5-HT 2A receptors in cell-based functional assays. ACP-204 had 13-fold less affinity for 5-HT 2C receptors in radioligand binding, and 30-100 fold less potency at 5-HT 2C in the functional assays, and was over 1000-fold selective against over 70 other targets. ACP-204 had 9-fold lower potency inhibiting hERG than pimavanserin, and lower potency at Cav1.2 L-type calcium and Nav1.5 sodium channels, all channels associated with cardiovascular function. ACP-204 was active in three rodent models of schizophrenia, was orally active, and potently engaged with central 5-HT 2A receptors in non-human primates. Long-term toxicity studies demonstrated wide safety margins, and pharmacokinetic modeling predicted a 14.7 – 21.7 h half-life in humans. It is anticipated that reducing the potential for QT prolongation will allow greater dosing flexibility with ACP-204 compared with pimavanserin; additionally, a shorter half-life may provide faster onset of action due to plasma concentrations reaching steady-state sooner. ACP-204 is currently being evaluated for efficacy and safety in Alzheimer's disease psychosis and Lewy Body Dementia psychosis.