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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / chemistry
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Analgesics / metabolism
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Analgesics / pharmacology
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Analgesics / therapeutic use
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Animals
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Binding Sites
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Cell Line
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Cell Survival / drug effects
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Chronic Pain / drug therapy
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Chronic Pain / pathology
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Dogs
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Half-Life
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Humans
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Ligands
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Male
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Mice
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Molecular Docking Simulation
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Mutagenesis, Site-Directed
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NAV1.7 Voltage-Gated Sodium Channel / chemistry*
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NAV1.7 Voltage-Gated Sodium Channel / genetics
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NAV1.7 Voltage-Gated Sodium Channel / metabolism
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Rats
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Structure-Activity Relationship
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Sulfonamides / chemistry*
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Sulfonamides / metabolism
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use
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Voltage-Gated Sodium Channel Blockers / chemistry*
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Voltage-Gated Sodium Channel Blockers / metabolism
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Voltage-Gated Sodium Channel Blockers / pharmacology
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Voltage-Gated Sodium Channel Blockers / therapeutic use
Substances
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Analgesics
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Ligands
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NAV1.7 Voltage-Gated Sodium Channel
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Protein Isoforms
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SCN9A protein, human
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Sulfonamides
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Voltage-Gated Sodium Channel Blockers