PF-02545920 / Pfizer - LARVOL DELTA

Inhibition of Phosphodiesterase 10A by MP-10 Rescues Behavioral Deficits and Normalizes Microglial Morphology and Synaptic Pruning in A Mouse Model of FOXP1 Syndrome. (PubMed, Adv Sci (Weinh)) - "Interestingly, treatment of Foxp1± mice with the PDE10A antagonist MP-10 (PF-2545920) immediately after birth not only corrects behavioral abnormalities, including decreased ultrasonic vocalization, hyperactivity, and anxiety but also normalizes changes in microglia morphology and synaptic pruning. Transcriptomic analysis with a neuroinflammation-specific gene panel reveals nominal gene expression changes after MP-10 treatment, including Bdnf upregulation and enrichment of neurotrophin signaling. Since FOXP1 and its signaling pathway are highly conserved, administration of MP-10 or other Pde10a antagonists may also alleviate the neurological dysfunction seen in humans with FOXP1 syndrome."

Journal • Preclinical • Developmental Disorders • Inflammation • Mental Retardation • Mood Disorders • Psychiatry • ACYP1 • CD74 • FOXP1 • LINC00473

Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice. (PubMed, Anesthesiology) - "Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs."

Journal • Preclinical • Pain • ACYP1 • LINC00473

MK-8189, a PDE10A inhibitor, for the treatment of schizophrenia (ECNP 2023) - P2b | "Efficacy results from previous proof-of-concept clinical trials with PF-02545920 and TAK-063 in individuals with acute psychosis have been unimpressive but their enzyme inhibition over 24 hours was likely modest ( 80% trough EO. Consequently, doses up to 24mg, predicted to produce > 80% sustained EO, are being evaluated in an ongoing Phase 2b trial [NCT04624243]."

CNS Disorders • Dystonia • Psychiatry • Schizophrenia • ACYP1 • LINC00473

Phosphodiesterase 10A inhibitor PF-2545920 as a prospective agent for the clinical promotion of sperm motility. (PubMed, Asian J Androl) - "However, the most commonly reported nonselective PDE inhibitor pentoxifylline and PDE5 inhibitor sildenafil have the disadvantages of requiring a high concentration and destroying sperm integrity. PF-2545920 also increased mitochondrial membrane potential (P < 0.001) and altered intracellular calcium (P < 0.05) in a dose-dependent manner, including increasing sperm hyaluronic acid penetrating ability (P < 0.05). Therefore, PF-2545920 might be an excellent choice for stimulating the sperm motility."

Journal

Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer. (PubMed, J Ovarian Res) - "Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis...We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced β-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment."

Journal • Immunology • Inflammation • Oncology • Ovarian Cancer • Solid Tumor • EGF • LINC00473

Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition. (PubMed, Int J Mol Sci) - "In particular, a combination comprising the MRP1 inhibitor reversan, PF-2545920 and MY-5445, all at low micromolar concentrations, afforded nearly complete inhibition of glioblastoma cell growth. Thus, the potent suppression of glioblastoma cell viability may be achieved by combining MRP1 inhibitors with PDE inhibitors at a lower toxicity than that of the standard chemotherapeutic agents, thereby providing a new combination therapy for this challenging malignancy."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • ABCC1

[VIRTUAL] Metabolic Drug Survey Highlights Cancer Cell Dependencies and Vulnerabilities (ASH 2020) - "Unsupervised hierarchical clustering of the drug sensitivity profiles stratified the cell lines in 5 functional taxonomic groups, with the activity of 19 compounds significantly contributing to the cell line grouping (e.g. PF-02545920, GW 4064, mTOR inhibitors, daporinad)...Genotype to phenotype associations were identified between FLT3mutations and sensitivity to 5-FU, lestaurtinib, and PF-02545920...Selective sensitivities were detected to the lactate transporter (SLC16A1) inhibitor AZD3965, the PI3K inhibitor pictilisib, and the fatty acid synthase inhibitor GSK2194069, which could be explained by varied gene expression in sensitive cell lines and target/process dependency. CLIMET allows for identification of metabolic susceptibilities, grouping of cancer cells based on metabolic dependencies, as well as understanding of context-dependent mechanism of action of drugs. Functional drug testing may provide a rapid and robust approach to identify metabolic..."

Hematological Malignancies • Leukemia • Oncology • FASN • MCT1

The Potent PDE10A Inhibitor MP-10 (PF-2545920) Suppresses Microglial Activation in LPS-Induced Neuroinflammation and MPTP-Induced Parkinson’s Disease Mouse Models. (PubMed, J Neuroimmune Pharmacol) - "These data collectively suggest that MP-10 may have therapeutic potential in PD and other neuroinflammatory disorders. Graphical Abstract."

Journal • Preclinical • CNS Disorders • Gene Therapies • Huntington's Disease • Immunology • Movement Disorders • Parkinson's Disease • IL10 • IL6 • MAPK8 • NFE2L2 • NFKB1 • PCR • TNFA

Effect of phosphodiesterase (1B, 2A, 9A and 10A) inhibitors on central nervous system cyclic nucleotide levels of rats and mice. (PubMed, Neurochem Int) - "Male Sprague Dawley (Crl:CD [SD]) rats were dosed subcutaneously (sc) with a PDE1B inhibitor (DNS-0056), a PDE2A inhibitor (PF-05180999), a PDE9A inhibitor (PF-4447943), and a PDE10A inhibitor (MP10), each at a single dose of 10 or 30 mg/kg, or concomitantly with all 4 inhibitors at 10 mg/kg each...The drug exposures after concomitant treatment were also higher than in the individual inhibitor-treated animals. cGMP enhancement could be due to synergistic effects, though an additive effect of the combined inhibitor concentrations may also contribute."

Biomarker • Journal • Preclinical • CNS Disorders

Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models. (PubMed) - Neuron - "Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits."

Journal • Biosimilar

An inpatient study of the efficacy, safety, and tolerability of PF-02545920 in the treatment of acute exacerbation of schizophrenia (clinicaltrials.gov) - P2, N=260

Schizophrenia

An inpatient study of the efficacy, safety, and tolerability of PF-02545920 in the treatment of acute exacerbation of schizophrenia (clinicaltrials.gov) - P2, N=259; Recruiting -> Completed

Trial completion • Schizophrenia

Randomized, Placebo Controlled Study Of The Efficacy And Safety Of PF-02545920 In Subjects With Huntington's Disease (clinicaltrials.gov) - P2; N=260; Recruiting; Sponsor: Pfizer; Trial primary completion date: Jun 2016 ➔ Oct 2016

Trial primary completion date • Biosimilar

Pfizer Pipeline: February 28, 2013 (Pfizer) - Projects discontinued from development since November 8, 2012 includes PF-02545920 and PF-05180999 for schizophrenia.

Discontinued • Schizophrenia

Phosphodiesterase 10A Inhibitor Monotherapy Is Not an Effective Treatment of Acute Schizophrenia. (PubMed, J Clin Psychopharmacol) - "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."

Journal • Monotherapy

A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia. (PubMed, J Clin Psychopharmacol) - "Current data and results of a prior monotherapy study in which PF-02545920 failed to differentiate from placebo refute the hypothesis that PDE10A inhibitors have use as antipsychotic agents for schizophrenia."

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