Discovery of a novel class of benzazepinone Nav1.7 blockers: Potential treatments for neuropathic pain

Hoyt, Scott B.; London, Clare; Gorin, David J.; Wyvratt, Matthew J.; Fisher, Michael H.; Abbadie, Catherine; Felix, John P.; García, María L.; Li, Xiaohua; Lyons, Kathryn A.; McGowan, Erin; MacIntyre, D. Euan; Martin, William J.; Priest, Birgit T.; Ritter, Amy M.; Smith, McHardy M.; Warren, Vivien A.; Williams, Brande S.; Kaczorowski, Gregory J.; Parsons, William H.

doi:10.1016/j.bmcl.2007.05.076

Cited by 70 publications

(35 citation statements)

References 19 publications

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“…Importantly, although CDA54 blocks Na v 1.2, Na v 1.5, Na v 1.7 and Na v 1.8 channels at roughly the same range of concentrations in vitro, CDA54 showed significantly lower CNS side effects and cardiotoxicity than mexilitine. Another recent study, also from Merck Research Laboratories (NJ, USA), described a benzazepinone compound with affinity for Na v 1.7 that has potential for reducing neuropathic pain [173]. By screening a large number of benzazepinone analogs, a compound that was a potent state-dependent blocker of inactivated Na v 1.7 channels and showed oral efficacy in a rat nerve injury model of neuropathic pain was discovered.…”

Section: Future Drugs and Directionsmentioning

confidence: 97%

Voltage-gated sodium channel blockers for the treatment of neuropathic pain

Cummins¹,

Rush²

2007

Expert Review of Neurotherapeutics

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Pain serves a crucial physiological function, warning the body of impending or actual tissue damage, preventing further damage and aiding the healing process. Neuropathic pain, resulting from nervous system injury or dysfunction, can be a serious medical problem and especially difficult to treat. Although sodium channel blockers are clinically useful for treating pain, they often provide only partial relief and adverse effects associated with nonspecific actions can limit their use. Research on the roles of sodium channels in neuronal excitability and pain shows that specific sodium channel isoforms are crucial determinants of nociception and neuropathic pain, indicating that it should be possible to develop sodium channel blockers with lower toxicity and enhanced efficacy for treating neuropathic pain.

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Section: Future Drugs and Directionsmentioning

confidence: 97%

Voltage-gated sodium channel blockers for the treatment of neuropathic pain

Cummins¹,

Rush²

2007

Expert Review of Neurotherapeutics

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“…It is suggested that this toxin has a novel binding site that is coupled with activation of the sodium channel [176,241,242]. Voltage-dependent reversal of the ProTX-II effect is more rapid for cardiac Na v 1.5 channels in comparison to other subtypes [243].…”

Section: Spider Toxinsmentioning

confidence: 99%

“…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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“…Аміди 3-бутенової кислоти знаходять застосу-вання в синтезі низки бензазепінонів, які є важли-вими об'єктами медичної хімії [35][36][37][38][39][40] (схема 25).…”

Section: синтез 7-та 8-членних лактамівunclassified

Heterocyclization of amides of alkenylcarboxylic acids

Tsyzoryk¹,

Васькевич²,

Вовк³

2015

J. org. pharm. chem.

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(Ховейда, Граббса, Нолана), реакції мета-тезису, а також радикальних процесів у регіо-та стереоселективних циклізаціях амідів у м'яких умовах. Розглянуті синтетичні варіанти носять загальний характер і дозволяють поряд із процесами циклізації здійснювати спрямовану функціоналізацію O-, N-, S-вмісних малих та середніх гетероциклічних систем. HETEROCYCLIZATION OF AMIDES OF ALKENYLCARBOXYLIC ACIDS N.M.Tsyzoryk, A.I.Vaskevich, M.V.Vovk Key words: amides of alkenylcarboxylic acids; electrophilic intramolecular cyclization; lactones; lactams The latest published data on heterocyclization of amides of alkenylcarboxylic acids have been systematized. It has been proven that the electrophilic intramolecular cyclization reaction of functionally substituted olefins opened in the 70s of the last century is a convenient way of constructing different oxygen-, nitrogen-and sulfurcontaining heterocyclic compounds. It has been noted that anilides of unsaturated carboxylic acids as bifunctional nucleophilic systems containing alkenyl and aminocarbonyl functions are useful models to study the electrophilic cyclization reaction, which leads to formation of O-and N-containing heterocycles (lactones and lactams). The last of them belong to the important types of compounds used as key blocks in the synthesis of biologically active alkaloids and their analogues, pharmaceutical and agrochemical products. The effective approaches to the synthesis of new types of functionalized lactones and lactams have been developed; amides of 3-butenoic, 4-pentenoic and 5-hexenoic acids are often used as substrates for their design. Along with classical methods of synthesis of lactones and lactams the literary sources relating to the use of original catalytic electrophilic systems (Nolan, Grubbs, Hoveyda), the metathesis reaction and radical processes in regio-and stereoselective cyclization of amides under mild conditions have been analyzed and summarized in the article. The synthetic versions considered are general in nature and allow to perform the targeted functionalization of O-, N-, S-containing heterocyclic small and medium-sized systems along with the cyclization processes. ГЕТЕРОЦИКЛИЗАЦИИ АМИДОВ АЛКЕНИЛКАРБОНОВЫХ КИСЛОТ

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Discovery of a novel class of benzazepinone Nav1.7 blockers: Potential treatments for neuropathic pain

Cited by 70 publications

References 19 publications

Voltage-gated sodium channel blockers for the treatment of neuropathic pain

Voltage-gated sodium channel blockers for the treatment of neuropathic pain

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Heterocyclization of amides of alkenylcarboxylic acids

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