Payne Claire Elizabeth, Brown Adam R, Theile Jonathon W, Loucif Alexandre J C, Alexandrou Aristos J, Fuller Mathew D, Mahoney John H, Antonio Brett M, Gerlach Aaron C, Printzenhoff David M, Prime Rebecca L, Stockbridge Gillian, Kirkup Anthony J, Bannon Anthony W, England Steve, Chapman Mark L, Bagal Sharan, Roeloffs Rosemarie, Anand Uma, Anand Praveen, Bungay Peter J, Kemp Mark, Butt Richard P, Stevens Edward B
Neusentis UK, Pfizer Global R&D, Cambridge, UK.
Br J Pharmacol. 2015 May;172(10):2654-70. doi: 10.1111/bph.13092. Epub 2015 Apr 10.
NaV 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 Nav 1.8 channel blocker of novel chemotype.
The inhibition of Nav 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.
PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50 : 331 nM) and in recombinantly expressed h Nav 1.8 channels (IC50 : 196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav 1.5 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 Nav 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.
Using PF-01247324, we have confirmed a role for Nav 1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav 1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons.
Nav 1.8离子通道已成为设计用于治疗慢性疼痛的低分子量阻滞剂的重要分子靶点。在此，我们描述了PF-01247324（一种新型化学类型的新一代选择性口服生物可利用的Nav 1.8通道阻滞剂）的作用。
使用体外膜片钳电生理学研究PF-01247324对Nav 1.8通道的抑制作用，并使用炎症性和神经性疼痛的体内啮齿动物模型证明其口服生物利用度和抗伤害感受作用。
PF-01247324抑制人背根神经节（DRG）神经元中的天然河豚毒素抗性（TTX-R）电流（IC50：331 nM）和重组表达的hNav 1.8通道（IC50：196 nM），对重组表达的TTX-R hNav 1.5通道（IC50：约10 μM）具有50倍的选择性，对河豚毒素敏感（TTX-S）通道（IC50：约10 - 18 μM）具有65 - 100倍的选择性。小直径啮齿动物DRG神经元中的天然TTX-R电流被IC50 448 nM抑制，并且人重组Nav 1.8通道和大鼠DRG神经元的TTX-R的阻断均具有频率和状态依赖性。体外电流钳显示PF-01247324降低了大鼠和人DRG神经元的兴奋性，并且还改变了动作电位的波形。在啮齿动物中的体内实验证明了在炎症性和神经性疼痛模型中的疗效。
使用PF-01247324，我们证实了Nav 1.8通道在炎症性和神经性疼痛中的作用。我们还证明了Nav 1.8通道在大鼠和人DRG神经元动作电位上升和重复放电中的关键作用。
