Advances in the discovery of selective NaV1.8 inhibitors for pain management

Pain management remains an unmet healthcare need, particularly in the development of effective non-opioid analgesics with improved safety profiles. Among emerging molecular targets, the voltage-gated sodium channel NaV1.8 has garnered significant attention due to its pivotal role in pain signaling. VX-548 (also known as suzetrigine), one of the most promising NaV1.8 inhibitors, has demonstrated encouraging clinical efficacy and received FDA approval in January 2025. This milestone has further stimulated strong interest from pharmaceutical companies worldwide, driving ongoing research efforts to identify novel chemical scaffolds and optimize structure-activity relationships (SARs) for improved potency, selectivity, and drug-like properties. In this review, we provide a comprehensive overview of recent progress in the discovery and development of selective NaV1.8 inhibitors, highlighting findings from patents and literature, chemical optimization strategies, and reported in vitro and in vivo pharmacological data. We also discuss current challenges and future opportunities in advancing NaV1.8 inhibitors as a transformative therapeutic approach for pain management.