PF-04449613 is a potent and selective cGMP-competitive PDE9A inhibitor (IC50 = 24 nM; IC50 >800 nM against other PDE members), displaying more than 1000-fold selectivity over the majority of 79 non-PDE targets investigated with the exception of cytochrome P450 2C19 (IC50 = 1600 nM), dopamine transporter (Ki = 110 nM), μ-opioid receptor (Ki = 3500 nM), and sodium channel binding site 2 (Ki = 470 nM). PF-4449613 is shown to effectively increase cGMP levels in brain (1-10 mg/kg s.c.; mice) and CSF (1-32 mg/kg s.c.; rats and cynomolgus macaques) in vivo with good brain penetration (brain/plasma ratio of 0.8 in mice). PF-04449613 is effective against D-amphetamine-induced auditory gating deficit (by 43% with 1 mg/kg PF-04449613 s.c.; 1 mg/kg AMP i.v.) and transverse aortic constriction-caused cardiac dysfunction (30 mg/kg/12 h p.o.) in mice in a NOS-independent manner.
Journal of medicinal chemistry, 55(21), 9055-9068 (2012-10-03)
Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments
The Journal of pharmacology and experimental therapeutics, 341(2), 396-409 (2012-02-14)
Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we
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