PF-04447943, also known as edelinontrine, is a selective, brain-penetrant phosphodiesterase 9A (PDE9A) inhibitor developed by Pfizer. Its molecular formula is C20H25N7O2, and the PF-04447943 molecular weight is 395.46 g/mol. The IUPAC name is 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(oxan-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one.
Application of PF-04447943
PF-04447943 is used to investigate PDE9A-dependent cGMP signaling in neural systems relevant to synaptic plasticity and memory. It supports recombinant-enzyme profiling, cellular cGMP assays, hippocampal plasticity experiments, and preclinical target-engagement studies. Its development history also allows comparison of rodent findings with clinical outcomes.
In Vitro
PF-04447943 inhibited recombinant PDE9A with Ki values of 2.8 nM for human, 4.5 nM for rhesus, and 18 nM for rat enzyme. For other PDEs, values ranged from 5.3 to more than 99 μM. The closest value, for PDE6C, corresponds to approximately 1,900-fold selectivity over human PDE9A.
In HEK293 cells expressing rhesus PDE9A2 and human NPR1, the compound showed an IC50 of 375 nM in an ANP-stimulated cGMP assay. In cultured hippocampal neurons, 30–100 nM increased neurite outgrowth and synapsin-1 expression, whereas 300–1,000 nM did not. It also facilitated weak-stimulus long-term potentiation at 100 nM, but not at 30 or 300 nM.
In Vivo
Oral administration of 1–30 mg/kg increased cerebrospinal-fluid cGMP in rats, supporting central target engagement. Doses of 1–3 mg/kg improved performance in three rodent cognition paradigms, including scopolamine-impaired novel object recognition. Reported rat pharmacokinetic values included a 4.9-hour half-life and a Tmax of 0.3 hours.
The Pfizer PF-04447943 program reached a 12-week Phase 2 trial in mild-to-moderate Alzheimer’s disease. Participants received 25 mg twice daily (n=91) or placebo (n=100). Adjusted ADAS-cog changes were −1.91 and −1.60, a nonsignificant difference of −0.31. NPI and global-impression outcomes also showed no significant benefit. The compound remains investigational.
Biochemical and Physiological Actions
PDE9A hydrolyzes cGMP and limits cGMP-dependent signaling. By inhibiting the active site, PF-04447943 reduces cGMP breakdown and can increase cGMP in relevant systems. The defined stereochemistry of the PF-04447943 molecular structure is part of its chemical identity. Cellular outcomes depend on concentration, model, and stimulation protocol, as shown by the non-linear neurite and potentiation responses.
Features and Benefits of PF-04447943
- Nanomolar biochemical potency against human, rhesus, and rat PDE9A
- Wide measured selectivity margins over other phosphodiesterase families
- Brain exposure and CSF cGMP target-engagement data in rodents
- Defined PF-04447943 chemical structure with published preclinical and Phase 2 results
PF-04447943 is a well-characterized research tool for PDE9A and cGMP studies, but its preclinical cognitive effects did not translate into efficacy in the reported Alzheimer’s trial. Before use, verify the PF-04447943 structure, assay value, and lot-specific documentation against the product CoA.
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