• SyncroPatch 384/768i

    全球最高通量的全自动膜片钳系统
  • SyncroPatch 384/768i

    平行记录384个细胞 => 最高可升级到768个
  • SyncroPatch 384/768i

    真正的高通量与GΩ级封接
  • SyncroPatch 384/768i

    Analysis Software even more powerful than before
  • SyncroPatch 384/768i

    高科技保证实验的灵活性

2019 - Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain

icon sp96   SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) publication in Journal of Medicinal Chemistry (2019)

Authors:
McKerrall S.J., Nguyen T., Lai K.W., Bergeron P., Deng L., DiPasquale A., Chang J.H., Chen J., Chernov-Rogan T., Hackos D.H., Maher J., Ortwine D.F., Pang J., Payandeh J., Proctor W.R., Shields S.D., Vogt J., Ji P., Liu W., Ballini E., Schumann L., Tarozzo G., Bankar G., Chowdhury S., Hasan A., Johnson J.P. Jr., Khakh K., Lin S., Cohen C.J., Dehnhardt C.M., Safina B.S., Sutherlin D.P.

Journal:
Journal of Medicinal Chemistry (2019) 62 (8): 4091-4109 DOI: 10.1021/acs.jmedchem.9b00141


Abstract:

Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Nav1.7. Compound 24 showed a robust PK/PD response in a Nav1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.

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