A novel selective and orally bioavailable Nav1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability

Background and PurposeNa(V)1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Na(v)1.8 channel blocker of novel chemotype. Experimental ApproachThe inhibition of Na(v)1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain. Key ResultsPF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50: 331nM) and in recombinantly expressed h Na(v)1.8 channels (IC50: 196nM), with 50-fold selectivity over recombinantly expressed TTX-R hNa(v)1.5 channels (IC50: approximate to 10M) and 65-100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50: approximate to 10-18M). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448nM, and the block of both human recombinant Na(v)1.8 channels and TTX-R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF-01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models. Conclusions and ImplicationsUsing PF-01247324, we have confirmed a role for Na(v)1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Na(v)1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.