PF-05180999 / Pfizer - LARVOL DELTA

Characterization of two novel phosphodiesterase 2 inhibitors Hcyb1 and PF-05180999 on depression- and anxiety-like behavior. (PubMed, Int J Neuropsychopharmacol) - "The results extend the previous studies and validate that PDE2A is a tractable target for drug development in the treatment of emotional disorders such as depression and anxiety."

Journal • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Psychiatry

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

A study of the safety, tolerability and pharmacokinetics of single doses of PF-05180999 in healthy adults (clinicaltrials.gov) - P1, N=29; Recruiting -> Completed; Completion date: Apr 2012 -> Dec 2011

Completion date • Trial completion • Schizophrenia

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

Discontinued • Schizophrenia

Enhancement of Synaptic Plasticity by Combination of PDE2 and PDE9 Inhibition Presumably via Pre- And Post-Synaptic Mechanisms (SIRS 2020) - "Moreover, the PDE2 inhibitor PF-05180999 (Helal et al., 2018) was characterized regarding enhancement of hippocampal LTP and further investigated in combination with the PDE9 inhibitor Bay 73-6691 (Wunder et al., 2005) for potential synergistic effects on LTP...Corroborating previous findings, PDE2 inhibition improves synaptic plasticity as shown by enhanced LTP. Moreover, for the first time, we could show that the combination of a PDE2 with a PDE9 inhibitor acts synergistically on improvement of synaptic plasticity as demonstrated by the shift from early into late LTP, which is considered to be a crucial mechanism for memory formation."

Target Engagement of a Phosphodiesterase 2 (PDE2) Inhibitor Affecting Long-Term Memory in the Rat. (PubMed, J Pharmacol Exp Ther) - "Previous preclinical studies demonstrated that PDE2A inhibitors could reverse N-methyl-D-aspartate receptor antagonist (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine or ketamine-induced memory deficit. Here, we report that the potent and selective PDE2A inhibitor 4-(1-azetidinyl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl]-imidazo[5,1-f][1,2,4]triazine (PF-05180999) enhances long-term memory in a contextual fear conditioning model in the rat at the oral dose of 0.3 mg/kg...Our results also suggest that when evaluating target occupancy of enzymes, potential regulation of enzyme activities should be considered. SIGNIFICANCE STATEMENT: N/A."

Journal • Preclinical