Discovery of Novel 2-(2-Benzimidazole)-Substituted Tetrahydrofur-ans as Potent and Selective NaV1.8 Inhibitors for the Treatment of Pain.

Selective inhibition of voltage-gated sodium channel 1.8 (NaV1.8) is a validated non-opioid analgesic strategy. Guided by the well-documented metabolic features of marketed VX-548 in humans and rats, we conducted rational structural optimization to circumvent its major reported metabolic pathways while preserving target potency, which afforded lead compound 31 with nanomolar NaV1.8 potency and favorable subtype selectivity. In male rats, it shows favorable oral bioavailability and >10-fold higher plasma AUC than VX-548, accompanied by potent analgesic efficacy. Favorable and consistent pharmacokinetic profiles are also observed in beagle dogs and cynomolgus monkeys, supporting its balanced cross-species metabolic behavior. Compound 31 also displays a favorable safety profile with no genotoxicity and weak hERG inhibition. Collectively, compound 31 represents a promising metabolically optimized lead for further preclinical evaluation.