Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia
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Acknowledgments
We appreciate Zhiqiang Liao, Ying Chen from Biology Department of WuXi AppTec for their bioassay support. This work was supported by National Natural Science Foundation of China (NO.81473188).
References (25)
- et al.
SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes
Neuron
(2006) - et al.
Recent progress in sodium channel modulators for pain
Bioorg Med Chem Lett
(2014) - et al.
The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Nav1.7
Bioorg Med Chem Lett
(2014) - et al.
Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice
Bioorg Med Chem Lett
(2017) - et al.
The discovery of tetrahydropyridine analogs as hNav1.7 selective inhibitors for analgesia
Bioorg Med Chem Lett
(2017) - et al.
Structure and activity relationship in the (S)-N-chroman-3-ylcarboxamide series of voltage-gated sodium channel blockers
Bioorg Med Chem Lett
(2012) Structure and function of voltage-gated ion channels
Annu Rev Biochem
(1995)- et al.
Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist
Science
(2015) Pain market
Nat Rev Drug Discov
(2010)- et al.
An SCN9A channelopathy causes congenital inability to experience pain
Nature
(2006)
Mutations in SCN9A, encoding a sodium channel a subunit, in patients with primary erythermalgia
J Med Genet
Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain
PLoS One
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2019, Computational Biology and ChemistryCitation Excerpt :The navigation channel is a large membrane protein containing four peripheral voltage sensor domains (VSD1-4) that affects the functional state of the central ion-conducting pore, which play prominent roles in a wide range of physiological function by controlling the open or closed state of Na+ ions-selective pores in response to changes in membrane potential and at least nine different voltage-dependent sodium channel subtypes (Nav1.1–1.9) have been found in the nervous system [10]. For mutations within the nine human Nav channel isoforms are associated with migraine (Nav1.1), epilepsy (Nav1.1–1.3, Nav1.6), pain (Nav1.7–1.9), cardiac (Nav1.5), and muscle paralysis (Nav1.4) syndromes [11,12]. For decades, the nerve blockade, an effective method for treating most pains, has relied on the inhibition of nine different voltage-dependent sodium channel subtypes (Nav1.1–1.9) carried by voltage-gated sodium channels.
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