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1.
Br J Pharmacol ; 172(10): 2654-70, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25625641

RESUMO

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.


Assuntos
Nociceptividade/efeitos dos fármacos , Ácidos Picolínicos/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Administração Oral , Animais , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Humanos , Potenciais da Membrana/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.8/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Ácidos Picolínicos/administração & dosagem , Ácidos Picolínicos/farmacocinética , Ratos , Tetrodotoxina/antagonistas & inibidores , Tetrodotoxina/farmacologia
2.
Bioorg Med Chem Lett ; 24(16): 3690-9, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25060923

RESUMO

Voltage-gated sodium channels (Navs) are an important family of transmembrane ion channel proteins and Nav drug discovery is an exciting field. Pharmaceutical investment in Navs for pain therapeutics has expanded exponentially due to genetic data such as SCN10A mutations and an improved ability to establish an effective screen sequence for example IonWorks Barracuda®, Synchropatch® and Qube®. Moreover, emerging clinical data (AZD-3161, XEN402, CNV1014802, PF-05089771, PF-04531083) combined with recent breakthroughs in Nav structural biology pave the way for a future of fruitful prospective Nav drug discovery.


Assuntos
Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio Disparados por Voltagem/metabolismo , Animais , Descoberta de Drogas , Humanos , Bloqueadores dos Canais de Sódio/química , Canais de Sódio Disparados por Voltagem/química
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