PF-01247324 is a selective and orally bioavailable Nav1.8 channel blocker with an IC50 of 196 nM for recombinant human Nav1.8 channel.
PF-01247324 inhibits native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50=331 nM) and in recombinantly expressed h Nav1.8 channels (IC50=196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav1.5 channels (IC50=10 uM) and 65-100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50=10-18 uM). In vitro current clamp shows that PF-01247324 reduces excitability in both rat and human DRG neurons and also alters the waveform of the action potential[1].
Experiments n rodents demonstrates efficacy in both inflammatory and neuropathic pain models. PF-01247324 reduces phase 2 flinching by 37% at 100 mg/kg. There is a significant effect of 30 mg/kg of PF-01247324 in the rat model carrageenan-induced thermal hyperalgesia and in CFA-induced mechanical hyperalgesia at exposures of 0.218 and 0.126 uM respectively[1]. Mice that received PF-01247324 shows significant improvements in motor coordination and cerebellar-like symptoms compared to control[2].
References:
[1]. Payne CE, et al. A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Br J Pharmacol. 2015 May;172(10):2654-70.
[2]. Shields SD, et al. Oral administration of PF-01247324, a subtype-selective Nav1.8 blocker, reverses cerebellar deficits in a mouse model of multiple sclerosis. PLoS One. 2015 Mar 6;10(3):e0119067.