RT Journal Article
SR Electronic
T1 A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.260869
DO 10.1124/jpet.119.260869
A1 Takeshi Enomoto
A1 Ayaka Tatara
A1 Masao Goda
A1 Yohei Nishizato
A1 Kantaro Nishigori
A1 Atsushi Kitamura
A1 Mami Kamada
A1 Shiori Taga
A1 Takashi Hashimoto
A1 Kazuhito Ikeda
A1 Yuki Fujii
YR 2019
UL http://jpet.aspetjournals.org/content/early/2019/10/02/jpet.119.260869.abstract
AB In our drug discovery program, we identified a novel orally-available and brain-penetrant phosphodiesterase 1 (PDE1) inhibitor, DSR-141562. In the present study, we characterized the preclinical profile of DSR-141562. This compound has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over other PDE families and 65 other tested biological targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the 3',5'-cyclic guanosine monophosphate (cGMP) concentration, and it potently enhanced the increase of cGMP induced by a dopamine D1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. 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. Further, DSR-141562 at 1-100 mg/kg did not induce any signs of catalepsy in rats. 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 the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia.SIGNIFICANCE STATEMENT This is the first paper showing that a phosphodiesterase 1B inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Further, we demonstrated that this compound improved cognitive function in the common marmoset, a non-human primate.