Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Nav1.8 sodium channel with efficacy in a model of neuropathic pain

Scanio, Marc J. C.; Shi, Lei; Drizin, Irene; Gregg, Robert J.; Atkinson, Robert N.; Thomas, James B.; Johnson, Matthew S.; Chapman, Mark L.; Liu, Dong; Krambis, Michael J.

doi:10.1016/j.bmc.2010.09.057

Cited by 33 publications

(20 citation statements)

References 36 publications

(46 reference statements)

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“…Although Na v inhibitory toxins from other species have yet to show preferential Na v 1.8 targeting, a chimeric scorpion toxin (drosotoxin) shows quite low potency but high selectivity for TTXresistant (Na v 1.8) versus TTX-sensitive Na v currents in rat sensory neurons . Consistent with results obtained using O-conotoxins, small-molecule antagonists preferentially targeting Na v 1.8 (Jarvis et al, 2007;Scanio et al, 2010) have since been reported to show efficacy in neuropathic pain models.…”

Section: F Sodium Channel Inhibition In Pain Managementsupporting

confidence: 76%

Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

385

424

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Section: F Sodium Channel Inhibition In Pain Managementsupporting

confidence: 76%

Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

385

424

View full text Add to dashboard Cite

“…Nav1.7 target anesthetics such as lidocaine have been found to be minimally effective at blocking cough. A lot of recent interest has been generated in Nav 1.8 as a target for both inflammatory and neuropathic pain with a few inhibitors being used in preclinical target validation [55–57]. Whether targeting Nav1.8 or Nav1.9 are effective at blocking unhelpful cough remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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Introduction: Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain.Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC. They review repurposed and new pharmacological treatments. Several meta-analyses were performed to compare the efficacy of treatments where possible.Expert opinion: Repurposed pain medications such as gabapentin and pregabalin reduce the frequency of cough and improve quality of life. Along with speech pathology, they are important and alternate treatments for refractory CC. However, more treatments are needed and the P2X3 ion channel receptor antagonists show the most promise. With a better understanding of neuronal activation and sensitisation and their signal processing in the brain, improved animal models of cough, and the use of validated cough measurement tools, more effective treatments will develop.

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“…While traditionally used for gastroesophageal reflux, this research suggests that HR2 antagonists may find clinical use in treating pain. Another study developed a novel set of pyrazine-based compounds to selectively block Nav 1.8 channels [74]. They tested oral administration of the compound in a rat model of neuropathic pain and noted dose-dependent pain-relief [74].…”

Section: Voltage-gated Sodium Channel Pharmacologymentioning

confidence: 99%

“…Another study developed a novel set of pyrazine-based compounds to selectively block Nav 1.8 channels [74]. They tested oral administration of the compound in a rat model of neuropathic pain and noted dose-dependent pain-relief [74]. Similar to the work of Rahman et al [71], Mert et al [75] compared the use of A-803467, a Nav 1.8 antagonist, to lidocaine in a rat model of diabetic neuropathy.…”

Section: Voltage-gated Sodium Channel Pharmacologymentioning

confidence: 99%

Pain transduction: a pharmacologic perspective

McEntire

Kirkpatrick

Dueck

et al. 2016

Expert Review of Clinical Pharmacology

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Pain represents a necessary physiological function yet remains a significant pathological process in humans across the world. The transduction of a nociceptive stimulus refers to the processes that turn a noxious stimulus into a transmissible neurological signal. This involves a number of ion channels that facilitate the conversion of nociceptive stimulus into an electrical signal. Because an understanding of nociceptive physiology complements a discussion of analgesic pharmacology, the relationships between the two are presented together. In this review article, a critical evaluation is provided on the findings relating to both the physiology and pharmacology of relevant acid-sensing ion channels (ASIC), and transient receptor potential (TRP) cation channels, and voltage-gated sodium (Nav) channels.

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Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Nav1.8 sodium channel with efficacy in a model of neuropathic pain

Cited by 33 publications

References 36 publications

Conus Venom Peptide Pharmacology

Conus Venom Peptide Pharmacology

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Pain transduction: a pharmacologic perspective

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