The Preclinical Profile of DSR-141562: A Novel Phosphodiesterase 1 Inhibitor for the Treatment of Positive Symptoms, Negative Symptoms and Cognitive Impairments Associated with Schizophrenia.

Abstract

We discovered a novel orally-available and brain-penetrant phosphodiesterase 1 (PDE1) inhibitor, DSR-141562.  This compound has high selectivity for the PDE1 family over other PDE families and 65 off-targets.  Further, it has the preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family isoforms.  Since PDE1B is believed to regulate dopaminergic and glutamatergic signal transduction, we evaluated the effects of this compound using schizophrenia-related behavioral assays.  DSR-141562 at 3-30 mg/kg potently inhibited methamphetamine-induced locomotor hyperactivity in rats, while it had only minimal effects on the spontaneous locomotor activity.  DSR-141562 at 0.3-3 mg/kg reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist phencyclidine, in mice and rats, respectively.  In common marmosets, DSR-141562 at 3 and 30 mg/kg improved success rate in the object retrieval with detour task.  DSR-141562 at 30 and 100 mg/kg potently elevated the cGMP concentration in monkey cerebrospinal fluid, which could be used as a translational biomarker.  These results suggest that DSR-141562 would have the therapeutic potential for positive symptoms, negative symptoms and cognitive impairments in schizophrenia.