Development and characterization of pyridyl carboxamides as potent and highly selective Nav1.8 inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2025-03, Vol.117, p.130059, Article 130059
• Main Authors: Poslusney, Michael, Ernst, Glen, Huang, Yifang, Gerlach, Aaron C., Chapman, Mark L., Santos, Sónia, Barrow, James C.
• Format: Article
• Language: English
• Subjects: Nav1.8; Pain; SCN10A; Sodium channel
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.130059

[Display omitted] •Nav1.8 inhibitors have demonstrated potential to be novel non-opiate analgesics.•Diaryl ether carboxamides show remarkably good selectivity for inhibiting Nav1.8 but have poor solubility and PK properties.•Strategic incorporation of the sulfoximine functional group results in improved solubility and overall properties.•Compound 42 is an optimized compound with a good combination of potency, selectivity, and pharmacokinetics. The voltage-gated sodium channel Nav1.8 (SCN10A) has strong genetic and pharmacological validation as a potential target for treating acute and chronic pain. While several different chemotypes have been advanced as selective inhibitors, a quinoxaline carboxamide core structure was identified as a particularly attractive core structure due to very high sodium channel subtype selectivity. However, poor solubility and overall ADME properties need to be improved. Scaffold hopping to a central trifluoromethyl pyridine followed by optimization of distal substituents resulted in improved overall properties. Several advanced lead compounds have been identified with excellent potency, selectivity, solubility, and pharmacokinetics. Preliminary mechanism of action studies suggest that this class of compounds are voltage and state independent inhibitors that bind to a novel site on the Nav1.8 channel.