Conformational restriction enables discovering a series of chroman derivatives as potent and selective Na1.8 inhibitors with improved pharmacokinetic properties.

Voltage-gated sodium channel 1.8 (Na1.8) is a promising analgesic target due to its unique biophysical characteristics and specific role in nociceptive sensation. VX-150 initially completed proof-of-concept studies in clinical trials, but with high dosages and frequent administration. Herein, based on VX-150, we report the design, synthesis and structure-activity relationship (SAR) study aiming to identify novel, potent and selective Na1.8 inhibitors with improved pharmacokinetic properties. Conformational restriction strategy and subsequent optimization led to the identification of the chroman derivative (R)-40 as the most promising hNa1.8 inhibitor showing an IC value of 5.9 ± 1.0 nM and good selectivity over other tested Na channels and hERG channel. More importantly, (R)-40 showed good in vitro metabolic stability in liver microsomes across multiple species and excellent in vivo PK profiles in rats and dogs. Notably, (R)-40 exerted dose-dependent analgesic activities in both rat models with postoperative and inflammatory pain, and a wide safety margin in neurotoxicity evaluation. Overall, these results confirmed conformational restriction as an effective strategy to improve PK profile, and our detailed study provided a valuable foundation for developing novel Na1.8 inhibitors.