GNE-616   Click here for help

GtoPdb Ligand ID: 10355

Synonyms: compound 24 [PMID: 30943032] | GNE616
Compound class: Synthetic organic
Comment: GNE-616 is an arylsulfonamide class voltage gated sodium channel inhibitor that is selective for the Nav1.7 isoform [5]. This class of inhibitors are channel blockers that bind to the fourth voltage sensing domain (VSD4) of the channel and lock it into the inactivated state [1,6]. Nav1.7 is a mechanistic target that is being pursued for the treatment of chronic pain [2-4,6-7].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 1
Rotatable bonds 6
Topological polar surface area 105.69
Molecular weight 537.15
XLogP 4.04
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES Fc1cc2c(cc1S(=O)(=O)Nc1ccncn1)OCCC2N1CCC(CC1c1ccccn1)C(F)(F)F
Isomeric SMILES Fc1cc2c(cc1S(=O)(=O)Nc1ccncn1)OCC[C@@H]2N1CC[C@@H](C[C@@H]1c1ccccn1)C(F)(F)F
InChI InChI=1S/C24H23F4N5O3S/c25-17-12-16-19(33-9-5-15(24(26,27)28)11-20(33)18-3-1-2-7-30-18)6-10-36-21(16)13-22(17)37(34,35)32-23-4-8-29-14-31-23/h1-4,7-8,12-15,19-20H,5-6,9-11H2,(H,29,31,32)/t15-,19-,20+/m0/s1
InChI Key XQUOWYVEKSXNET-RYGJVYDSSA-N
References
1. Bagal SK, Chapman ML, Marron BE, Prime R, Storer RI, Swain NA. (2014)
Recent progress in sodium channel modulators for pain.
Bioorg. Med. Chem. Lett., 24 (16): 3690-9. [PMID:25060923]
2. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y et al.. (2006)
An SCN9A channelopathy causes congenital inability to experience pain.
Nature, 444 (7121): 894-8. [PMID:17167479]
3. Gingras J, Smith S, Matson DJ, Johnson D, Nye K, Couture L, Feric E, Yin R, Moyer BD, Peterson ML et al.. (2014)
Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain.
PLoS ONE, 9 (9): e105895. [PMID:25188265]
4. Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, Fraser R, Young C, Hossain S, Pape T, Payne B, Radomski C, Donaldson G, Ives E, Cox J, Younghusband HB, Green R, Duff A, Boltshauser E, Grinspan GA, Dimon JH, Sibley BG, Andria G, Toscano E, Kerdraon J, Bowsher D, Pimstone SN, Samuels ME, Sherrington R, Hayden MR. (2007)
Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.
Clin. Genet., 71 (4): 311-9. [PMID:17470132]
5. McKerrall SJ, Nguyen T, Lai KW, Bergeron P, Deng L, DiPasquale A, Chang JH, Chen J, Chernov-Rogan T, Hackos DH et al.. (2019)
Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain.
J. Med. Chem., 62 (8): 4091-4109. [PMID:30943032]
6. McKerrall SJ, Sutherlin DP. (2018)
Nav1.7 inhibitors for the treatment of chronic pain.
Bioorg. Med. Chem. Lett., 28 (19): 3141-3149. [PMID:30139550]
7. Shields SD, Deng L, Reese RM, Dourado M, Tao J, Foreman O, Chang JH, Hackos DH. (2018)
Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors.
J. Neurosci., 38 (47): 10180-10201. [PMID:30301756]