A novel selective and orally bioavailable Na_v1.8 channel blocker, PF‐01247324, attenuates nociception and sensory neuron excitability

Abstract

BACKGROUND AND PURPOSENaV1.8 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 Nav1.8 channel blocker of novel chemotype. EXPERIMENTAL APPROACHThe inhibition of Nav1.8 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: 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 μM) and 65-100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50: ∼10-18 μM). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448 nM, and the block of both human recombinant Nav1.8 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 Nav1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves

“…As expected, PF-01247324, a drug that selectively blocks the TTX-resistant NaV 1.8 channels, had no effect on the cholinergic contractions (34 6 3% versus 35 6 3% in the absence and presence of 1 mM drug, respectively; n 5 6, P . 0.1) (Payne et al, 2015). NaV1 gene expression was detected in bronchial ganglia (n 5 11), but not in the juxtaposed non-neuronal tissue.…”

New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain

“…Both small molecule (McCormack et al, 2013) and biologic therapeutic approaches (Lee et al, 2014) are being used to gain sub-type selectivity, and clinical trials of selective Na v 1.7 blockers have begun in neuropathic pain conditions such as trigeminal neuralgia (Zakrzewska et al, 2013). Trials in DN are now starting and new Na v 1.8 blockers are under development for possible use in painful DN (Han et al, 2016; Payne et al, 2015). A particularly exciting prospect of VGSC blockers in painful DN would be if such therapy could be disease modifying given the potential role for these ion channels in axonal degeneration in circumstances of diabetes-mediated energetic stress.…”

Sodium channels in pain disorders: pathophysiology and prospects for treatment

“…The gain-of-function attributes that these mutations confer on Na v 1.8 include hyperpolarized voltage-dependence of activation, accelerated recovery from inactivation, enhanced ramp current and impaired inactivation. Na v 1.8 selective blockers have been developed and showed efficacy in animal models [65; 88], providing proof-of-principle that it is possible to target Na v 1.8 in vivo . The new links of Na v 1.8 in human pain disorders and success in pre-clinical studies using Na v 1.8 selective blockers suggest new therapeutic strategies when clinically-relevant blockers become available.…”