Design and synthesis of long-acting prodrugs of SEP-363856 with sustained antipsychotic-like activity.

Schizophrenia is a chronic and disabling neuropsychiatric disorder that requires sustained therapeutic exposure to achieve stable symptom control and prevent relapse. SEP-363856, a promising investigational antipsychotic, exhibits robust antipsychotic-like efficacy and safety; however, relatively high clearance may constrain the persistence of its pharmacological effects. To circumvent these drawbacks, three series of prodrugs of SEP-363856 featuring carbamate, amide, and sulfonamide linkages were designed and synthesized. In mouse liver microsomes, prodrug 15 showed markedly prolonged half-lives (57.8 min) relative to SEP-363856 (4.2 min), while gradually releasing the parent drug through metabolic conversion. In two mouse models of schizophrenia, SEP-363856 suppressed schizophrenia-like behaviors only through approximately 90 min, whereas prodrug 15 remained effective at later assessments up to approximately 150 min. These results collectively support prodrug design as a viable strategy for extending the antipsychotic-like effects of SEP-363856.