PF-04449613

PF-04449613 is a phosphodiesterase 9A (PDE9A) inhibitor (IC₅₀ = 22 nM).¹ It is selective for PDE9A over PDE1C (IC₅₀ = >1,000 nM), as well as over a variety of other PDEs, inhibiting PDE2-8, -10, and -11 activity by less than 30% in a panel of enzymes, ion channels, and transporters at 1 µM but does inhibit the human dopamine transporter (DAT; K_i = 293 nM). PF-04449613 (0.1-100 mg/kg, s.c.) increases cerebrospinal fluid (CSF) levels of cyclic GMP (cGMP) in rats. Subcutaneous administration of PF-04449613 (10 mg/kg) increases the rate of dendritic spine formation and elimination in mouse primary motor cortex pyramidal neurons in vivo.² It increases the average running speed of mice in an accelerating rotarod task, indicating improved motor learning, at the same dose.

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1. Claffey, M.M., Helal, C.J., Verhoest, P.R., et al. Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors. J. Med. Chem. 55(21), 9055-9068 (2012).

2. Lai, B., Li, M., Hu, A., et al. The phosphodiesterase 9 inhibitor PF-04449613 promotes dendritic spine formation and performance improvement after motor learning. Dev. Neurobiol. 78(9), 859-872 (2018).