Benzazepinone Nav1.7 blockers: Potential treatments for neuropathic pain

Hoyt, Scott B.; London, Clare; Ok, Hyun; Gonzalez, Edward J.; Duffy, Joseph; Abbadie, Catherine; Dean, Brian; Felix, John P.; García, María L.; Jochnowitz, Nina; Karanam, Bindhu V.; Li, Xiaohua; Lyons, Kathryn A.; McGowan, Erin; MacIntyre, D. Euan; Martin, William J.; Priest, Birgit T.; Smith, McHardy M.; Tschirret-Guth, Richard A.; Warren, Vivien A.; Williams, Brande S.; Kaczorowski, Gregory J.; Parsons, William H.

doi:10.1016/j.bmcl.2007.09.032

Cited by 43 publications

(31 citation statements)

References 19 publications

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“…Obstacles have plagued the development of VGSC inhibitors, ranging from non-specificity to blood brain barrier-impermeability, as well. A structurally novel benzodiazepine-based state-dependent Nav1.7 blocker, for example, exhibited poor pharmacokinetic properties and inefficacy against inflammatory pain states despite intravenous or intrathecal routes of administration [15–17]. While several other Nav1.7 inhibitors demonstrated high target affinity, low nanomolar affinity for other VGSC isoforms has been an insurmountable hurdle to date [18–20].…”

Section: Introductionmentioning

confidence: 99%

CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Chew

Khanna

2018

Neuronal Signaling

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Neuropathic pain represents a significant and mounting burden on patients and society at large. Management of neuropathic pain, however, is both intricate and challenging, exacerbated by the limited quantity and quality of clinically available treatments. On this stage, dysfunctional voltage-gated ion channels, especially the presynaptic N-type voltage-gated calcium channel (Cav2.2) and the tetrodotoxin-sensitive voltage-gated sodium channel (Nav1.7), underlie the pathophysiology of neuropathic pain and serve as high profile therapeutic targets. Indirect regulation of these channels holds promise for the treatment of neuropathic pain. In this review, we focus on collapsin response mediator protein 2 (CRMP2), a protein with emergent roles in voltage-gated ion channel trafficking and discuss the therapeutic potential of targeting this protein.

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Section: Introductionmentioning

confidence: 99%

CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Chew

Khanna

2018

Neuronal Signaling

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“…Compound XA from Xenon Pharmaceuticals, which was profiled using the [ 14 C]-guanidinium flux assay, showed 30-fold more affinity for the Na v 1.7 channel compared to other subtypes (Na v 1.1, Na v 1.3-1.6 and Na v 1.8) (Patent number WO-2007109324) [251,254]. Several benzazepinone and imidazopyridine derivatives, which were developed by Merck Research Laboratories, also selectively block the Na v 1.7 channel [241,255,256]. A-803467, a novel selective blocker of the Na v 1.8 channel, was discovered by Abbott Laboratories in 2007 [257].…”

Section: Synthetic Compoundsmentioning

confidence: 99%

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Andavan

Lemmens‐Gruber²

2011

CMC

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Voltage-gated sodium channels produce fast depolarization, which is responsible for the rising phase of the action potential in neurons, muscles and heart. These channels are very large membrane proteins and are encoded by ten genes in mammals. Sodium channels are a crucial component of excitable tissues; hence, they are a target for various neurotoxins that are produced by plants and animals for defence and protection, such as tetrodotoxin, scorpion toxins and batrachotoxin. Several mutations in various sodium channel subtypes cause multiple inherited diseases known as channelopathies. When these mutated sodium channel subtypes are expressed in various tissues, channelopathies in brain, skeletal muscle and cardiac muscle develop as well as neuropathic pain. In this review, we discuss aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels. In addition, we report novel mutations that underlie a spectrum of diseases, such as Brugada, long QT syndrome and inherited conduction disorders. Furthermore, this review explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of the channel subtypes.

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“…[137][138][139][140] The interaction of Compound 4 with Na v 1.7, Na v 1.8, and Na v 1.5 channels was further characterized in whole cell electrophysiology. Minimal block was observed when compound 4 was applied to hNa v 1.7 channels at Ϫ100 mV.…”

Section: Novel Na V 17 Blockers From Merckmentioning

confidence: 99%

“…When dosed orally at 10 mg/kg, Compound 32 elicited significant reversal of allodynia at 2 h postdose (% reversal). 139 In 2008, Merck scientists described a related series of imidazopyridines. 141 As for the parent benzazepinone series, several members of the imidazopyridine family exhibited modest selectivity for Na v 1.7 in comparison with Na v 1.8 (up to 7ϫ [e.g., Compound 43]).…”

Section: Novel Na V 17 Blockers From Merckmentioning

confidence: 99%

Sodium Channel Blockers for the Treatment of Neuropathic Pain

2009

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Summary:Drugs that block voltage-gated sodium channels are efficacious in the management of neuropathic pain. Accordingly, this class of ion channels has been a major focus of analgesic research both in academia and in the pharmaceutical/biotechnology industry. In this article, we review the history of the use of sodium channel blockers, describe the current status of sodium channel drug discovery, highlight the challenges and hurdles to attain sodium channel subtype selectivity, and review the potential usefulness of selective sodium channel blockers in neuropathic pain.

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Benzazepinone Nav1.7 blockers: Potential treatments for neuropathic pain

Cited by 43 publications

References 19 publications

CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Sodium Channel Blockers for the Treatment of Neuropathic Pain

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