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

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 D 1 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 schizophreniarelated 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.

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

“…A well-known inhibitor of PDE1B is DSR-141562, which inhibits locomotor hyperactivity and reverses social interaction and novel object recognition in normal mice and rats. This molecule was also shown to improve cognition in the marmoset, a non-human primate [ 59 ] by acting through CREB and DARPP32 [ 32 , 59 ] (Fig. 1 ).…”

“…1 ). DSR-141562 has been proposed as a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia [ 59 ].…”

The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation

“…Various phosphodiesterase (PDE) families are known to influence social behaviors ( Sano et al, 2008 ; Grauer et al, 2009a ; Alexander et al, 2016 ; Gurney et al, 2017 ; Maurin et al, 2018 ; Enomoto et al, 2019 ) or neuroinflammation ( Sebastiani et al, 2006 ; Peixoto et al, 2015 ; Schwenkgrub et al, 2017 ; Tibbo and Baillie, 2020 ; Ponsaerts et al, 2021 ); but evidence suggests the PDE11A family may be a key regulator of both. Although there are four isoforms of PDE11A, PDE11A4 is the longest and only isoform found in the brain ( Yuasa et al, 2001a ; Yuasa et al, 2001b ).…”

A genetic basis for friendship? Homophily for membrane-associated PDE11A-cAMP-CREB signaling in CA1 of hippocampus dictates mutual social preference in male and female mice

“…Here, we use mouse models to test the hypothesis that genetic similarities within the cAMP-hydrolyzing enzyme phosphodiesterase 11A (PDE11A) may be a key neurobiological mechanism underlying mutual social preference. Several PDE families are known to influence social interactions in rodents 28 – 30 , but PDE11A is particularly interesting in the context of mutual social preference. First, PDE11A expression in the brain is enriched in neurons of the ventral hippocampal formation, a brain region critical to social behaviors 31 , and deletion of Pde11a alters gene expression in the oxytocin signaling cascade (i.e., a key regulator of social bonding 32 ).…”