PF-02545920

MP-10 (PF-2545920) is a selective inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly enriched in the striatum, nucleus accumbens, olfactory tubercle, and substantia nigra. The therapeutic effect of MP-10 has been reported in psychiatric and neurodegenerative disorders such as schizophrenia, depression, and Huntington's disease. However, the effect of MP-10 in Parkinson's disease (PD) has not been reported to date. In this study, we examined the effect of MP-10 in neuroinflammation and PD mouse models. MP-10 inhibited nitric oxide, tumor necrosis factor alpha, and interleukin (IL)-6 production, while it promoted IL-10 production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Subsequent western blot and reverse transcription polymerase chain reaction analyses showed that MP-10 reduced the mRNA and protein levels of inducible nitric oxide synthase, cyclooxygenase-2, proinflammatory cytokines, and matrix metalloproteinase-3, -8, and - 9 in LPS-stimulated BV2 cells. Further mechanistic studies revealed that MP-10 exerts anti-inflammatory effects by inhibiting the phosphorylation of c-Jun N-terminal kinase and Akt, reducing the activity of nuclear factor-kappa B/activator protein-1, and upregulating the nuclear factor erythroid 2-related factor 2/antioxidant response element and protein kinase A/cAMP response element-binding protein signaling pathways. The anti-inflammatory effect of MP-10 was confirmed in vivo. Specifically, MP-10 inhibited microglial activation and proinflammatory gene expression in the brains of LPS-injected mice. Moreover, MP-10 rescued behavioral deficits and recovered dopaminergic neuronal cell death in the brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice. MP-10 also reduced microglial activation in this PD mouse model. These data collectively suggest that MP-10 may have therapeutic potential in PD and other neuroinflammatory disorders. Graphical Abstract.

Current treatments for psychotic symptoms associated with schizophrenia often provide inadequate efficacy with unacceptable adverse effects. Improved therapeutics have long been a goal of research. Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia.

The efficacy and safety of a highly selective PDE10A inhibitor, PF-02545920, was evaluated in a phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible patients (18–65 years) with an acute exacerbation of schizophrenia were randomized 2:2:1:2 to PF-02545920 (5 or 15 mg every 12 hours [Q12H] titrated), risperidone (3 mg Q12H), or placebo for 28 days (n = 74:74:37:74). The primary objectives were to evaluate the efficacy of PF-02545920 using the Positive and Negative Syndrome Scale (PANNS) and safety/tolerability.

At day 28, PF-02545920 (either dose) was not significantly different from placebo for mean change from baseline in the PANNS total score (primary end point) or most other end points. Pharmacokinetics exposures seemed adequate for binding/inhibiting PDE10A enzyme. Risperidone was statistically different from placebo for the PANNS total score, demonstrating study sensitivity. Incidence rates for adverse events were similar among the groups. Both doses of PF-02545920 were generally well tolerated. Dystonia occurred in 1, 6, 0, and 3 patients in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, respectively.

Neither dose of PF-02545920 was superior to placebo for the primary and most secondary end points. This indicates that PDE10A inhibition does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.