Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell’s plasma membrane. They are classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change (Voltage-gated, voltage-sensitive, or voltage-dependent sodium channel also called VGSCs or Nav channel) or a binding of a substance (a ligand) to the channel (ligand-gated sodium channels). Voltage-gated sodium (Nav) channels play a critical role in pain sensing and hyper-excitability, and Nav channel expressing neurons have been implicated in osteoarthritis pain. In particular, Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. The Nav1.7 channel has attracted attention as a pain target since the discovery that mutations in the SCN9A gene encoding for the Nav1.7 channel exhibit pain phenotypes.
PF-05186462 is a potent, selective and orally active blocker of human Nav1.7 voltage-dependent sodium channel. Again, PF-05186462 shows significant selectivity for Nav1.7 versus other sodium channels (Nav 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, and 1.8). In addition, PF-05186462 is moderately lipophilic and highly binds to plasma proteins. Moreover, this compound has a good aqueous solubility in vitro (>0.30 mg/mL). The pharmacokinetic results are as follows. After intravenous administration, the peak concentration of PF-05186462 appeared at the end of the 15-minute infusion. After oral administration, the Tmax is 1 hour and oral bioavailability is 101%. The geometric mean for total exposure (AUCinf) is approximately the same. Similarly, PF-05186462 shows the lowest plasma clearance values, being approximately 6% of hepatic blood flow.
To sum up, PF-05186462 is a selective and orally active Nav1.7 blocker with potential for acute or chronic pain research.