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A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated With Schizophrenia

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated With Schizophrenia

Takeshi Enomoto, Ayaka Tatara, Masao Goda, Yohei Nishizato, Kantaro Nishigori, Atsushi Kitamura, Mami Kamada, Shiori Taga, Takashi Hashimoto, Kazuhito Ikeda, Yuki Fujii

J Pharmacol Exp Ther. 2019 Dec;371(3):692-702.

PMID: 31578257

Abstract:

In our drug discovery program, we identified a novel orally available and brain-penetrant phosphodiesterase (PDE) 1 inhibitor, 3-methyl-7-(tetrahydro-2H-pyran-4-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]-methoxy}imidazo[5,1-f][1,2,4]triazin-4(3H)-one (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 biologic targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the 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. Furthermore, 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 1 inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Furthermore, we demonstrated that this compound improved cognitive function in the common marmoset, a nonhuman primate.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4245714	PDE1B active rat			Price

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