• SyncroPatch 384/768i

    世界最速のオートパッチ
  • SyncroPatch 384/768i

    384ch同時測定 => 768chへアップグレード可能
  • SyncroPatch 384/768i

    ギガシールによるHTS
  • SyncroPatch 384/768i

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

    最先端技術によるアッセイ柔軟性

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) 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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