PF-04447943 is an effective inhibitor of human recombinant PDE9A (IC50=12 nM). It has >78-fold selectivity, compared to other PDE family members (IC50>1000 nM).

PF-04447943 inhibits ANP (0.3 μM) stimulated cGMP (IC50: 375±36.9 nM (n=16)), in HEK whole cells expressing rhesus PDE9A2. PF-04447943 is found to be highly selective over other PDE enzymes (PDE1, Ki=8600±2121 nM, n = 5; PDE2A3, Ki>99,000 nM; PDE3A, Ki>50,000 nM; PDE4A, Ki>29,000 nM; PDE5A, Ki=14,980±5025 nM, n=5; PDE6C, Ki=5324±2612 nM, n=4; PDE7A2, Ki>75,000 nM; PDE8A, Ki>50,000 nM; PDE10, Ki>51,250±20,056 nM, n=4; PDE11, Ki>80,000 nM) and no other significant activity at ~60 other receptors/enzymes. Using recombinant human, rhesus, and rat PDE9A2 in a cell free assay PF-04447943 is shown to have a Ki of 2.8±0.26, 4.5±0.13, and 18.1±1.9 nM (n=4, 11 and 9 respectively) [2].

PF-04447943 concentrations dose-dependently increase in blood, brain, and cerebrospinal fluid (CSF), thirty minutes following oral administration in rats (1-30 mg/kg). In mice, PF-04447943 (3, 10, 30 mg/kg p.o.) dose-dependently enhances plasma and brain concentrations of PF-04447943 while the brain to plasma ratio ranged from 0.26 to 0.7 although this is not entirely dosed dependent. Based on i.v. and p.o. dosing, pharmacokinetic studies with PF-04447943 in the rat indicate a Tmax of 0.3 h, T1/2 of 4.9 h, Cl of 21.7 mL/min/kg, and oral bioavailability of 47%. The brain: plasma exposure ratios 30 min after dosing range from 0.13 at the 1 mg/kg dose to 0.33 at the 30 mg/kg dose. CSF levels are approximately 50% of brain levels. CSF cGMP levels increase in a dose-dependent manner from a basal level of 3 pmol/mL to 13.3 pmol/mL (3.5-fold) at the 30 mg/kg dose. CSF cGMP levels also increase in a dose-dependent manner from a basal level of 3 pmol/mL in vehicle-treated animals to 13.3 pmol/mL (3.5-fold) at the 30 mg/kg dose. CSF cGMP levels are elevated at all doses tested with a maximal effect of 3.5 fold increase above controls at 30 mg/kg [2].

1082744-20-4

C20H25N7O2

395.46

DMSO:54.6 mg/mL (138.07 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years