Preclinical Characterization of Selective Phosphodiesterase 10A Inhibitors: A New Therapeutic Approach to the Treatment of Schizophrenia

Abstract

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8: 54 -59, 2007 386 -396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

“…In line with this observation, the PDE10A inhibitor TP-10 with chemical structure similar to that of MP-10 also failed to improve PPI deficits in this strain (Schmidt et al, 2008). During assessment of expression changes in pathway-specific markers, PDE10A inhibition resulted in activation of both direct and indirect pathways (Grauer et al, 2009;Suzuki et al, 2015).…”

“…Given the high level of expression of PDE10A in MSNs, PDE10A inhibitors are thought to increase cyclic nucleotide levels and activate downstream signal transduction in the striatum, similar to D 2 antagonists in indirect pathway neurons. PDE10A inhibitors have also shown a promising pharmacological profile in rodents as therapeutic drugs for schizophrenia (Grauer et al, 2009;Megens et al, 2014;Schmidt et al, 2008;Smith et al, 2013). However, in a 4-week phase 2a proof-of-concept trial, Pfizer's PDE10A inhibitor MP-10 (PF-02545920) was not superior to placebo in patients with an acute exacerbation of their symptoms of schizophrenia (DeMartinis et al, 2012).…”

Novel Treatments of Psychosis

“…Papaverine, an opium alkaloid, was originally studied for its PDE10a inhibitory activity. Its use, however, was limited for clinical applications given its poor potency and short halflife after systemic administration [53]. New PDE10A inhibitors with more favorable characteristics are in various stages of development.…”

“…Inhibition of PDE10A is proposed to increase levels of these molecules and activate cAMP/PKA signaling in the indirect pathway. This is thought to inhibit the thalamocortical circuits thereby mimicking D 2 antagonism [53,54]. In direct pathway neurons, the activation of cAMP/PKA signaling is thought to reproduce D 1 agonist activity [54].…”

Discovery of novel PDE10 inhibitors by a robust homogeneous screening assay

“…Selective PDE10A inhibitors TP-10 and MP-10 have been reported to decrease psychomotor activity, reverse deficits in prepulse inhibition and inhibit conditioned avoidance response (CAR) in rodents, implying potential antipsychotic activities [11,12] . These compounds also improved cognitive performance in domains impaired in schizophrenia and negative symptoms in rodents [11][12][13] . As mentioned above, it is believed that novel PDE10 inhibitors would serve not only as potential drug candidates to treat psychosis, but also as important tools to elucidate the mechanisms of action related to PDE10.…”