Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties

Abstract

Voltage-gated sodium channel 1.8 (Na_V1.8) 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 Na_V1.8 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 hNa_V1.8 inhibitor showing an IC₅₀ value of 5.9 ± 1.0 nM and good selectivity over other tested Na_V 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 Na_V1.8 inhibitors.